Oxazolidinedione derivatives, their production and use

ABSTRACT

Novel 2,4-oxazolidinedione compounds of the formula: ##STR1## wherein R is a hydrocarbon residue or a heterocyclic group each of which may be substituted; Y is --CO--, --CH(OH)-- or --NR 3  -- (wherein R 3  is an alkyl group which may be substituted); m is 0 or 1; n is 0, 1 or 2; X is CH or N; A is bivalent straight or branched hydrocarbon chain residue having 1 to 7 carbon atoms; R 1  and R 2  each are hydrogen or an alkyl group, or R 1  and R 2  are combined with each other to form a 5- to 6-membered heterocyclic group optionally containing nitrogen; L and M each are hydrogen, or L and M are combined with each other to form a bond, or pharmaceutically acceptable salts thereof, having excellent hypoglycemic and hypolipidemic activities and are useful as anti-diabetics or hypolipidemic agents.

This application is a division of application Ser. No. 08/554,107, filedNov. 6, 1995 (now U.S. Pat. No. 5,665,748), which application is acontinuation of now abandoned application Ser. No. 08/201,021, filedFeb. 24, 1994 now abandoned.

This invention relates to a novel oxazolidinedione derivative having anaction of lowering blood sugar and lipid in blood, to a method ofproducing it and to an agent for the therapy of diabetes, which isuseful in the field of pharmaceuticals.

As remedies of diabetes, various biguanide compounds and sulfonylureacompounds have so far been used. However, biguanide compounds are hardlyused at present, since they cause lactic acidosis, while sulfonylureacompounds, which have a strong action of lowering blood sugar, oftencause severe hypoglycemia, requiring special attention in use. On theother hand, there are thiazolidinedione derivatives and oxazolidinedionederivatives known to have actions of lowering blood sugar and lipid inblood, which are free of such drawbacks.

For example, JPA H3(1991)-170478 and WO9202520-A1 describe, as2,4-oxazolidinedione derivatives having substituents at the 5-position,a series of 5-(substituted benzyl)-2,4-oxazolidinedione derivatives, JPBS62(1987)-30993 describes 2,4-oxazolidinedione derivatives substitutedwith alicyclic groups at the 5-position, and JPB S63(1988)-35632describes 2,4-oxazolidinedione derivatives substituted with, amongothers, a substituted aromatic ring at the 5-position.

The present inventors studied extensively on 2,4-oxazolidinedionederivatives, and found that novel derivatives having, as substituents atthe 5-position of 2,4-oxazolidinedione ring, a bivalent straight orbranched hydrocarbon chain residue substituted with phenyl or pyridyl,e.g. 2-(substituted phenyl or substituted pyridyl)ethyl group,3-(substituted phenyl or substituted pyridyl)propyl group,4-(substituted phenyl or substituted pyridyl)butyl group, 5-(substitutedphenyl or substituted pyridyl)pentyl group, etc., possess actions oflowering blood sugar and lipid in blood, thus the present inventionbeing completed.

More specifically, the present invention relates to:

1. a 2,4-Oxazolidinedione derivative represented by the general formula:##STR2## wherein R is a hydrocarbon residue or a heterocyclic group eachof which may be substituted; Y is --CO--, --CH(OH) or NR³ -- (wherein R³is an alkyl group which may be substituted); m is 0 or 1; n is 0, 1 or2; X is CH or N; A is bivalent straight or branched hydrocarbon chainresidue having 1 to 7 carbon atoms; R¹ and R² each are hydrogen or analkyl group, or R¹ and R² are combined with each other to form a 5- to6-membered heterocyclic group optionally containing nitrogen; L and Meach are hydrogen, or L and M are combined with each other to form abond, or a pharmaceutically acceptable salt thereof,

2. a medicinal composition comprising, as an effective component, a2,4-oxazolidinedione derivative represented by the general formula (I)or a pharmaceutically acceptable salt thereof,

3. a method for treating a mammal suffering from diabetes orhyperlipidemia, which comprises administering to the mammal an effectiveamount of a compound of the formula (I) or a pharmaceutically acceptablesalt thereof,

4. use of a compound of the formula (I) or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for the treatment of amammal suffering from diabetes or hyperlipidemia,

5. methods of producing a 2,4-oxazolidinedione derivative represented bythe general formula (I).

The compounds represented by the general formula (I) include compoundsshown by the following formulas (I-A1), (I-A2) and (I-A3). ##STR3##wherein each symbol has the meaning given above. Among the compounds(I-A1), (I-A2) and (I-A3), compounds (I-A1) and (I-A2) are preferable,and compounds (I-A1) are more preferable, in view of pharmacologicalactivity, toxicity and side effects. Compounds shown by the formula (I)wherein L and M are combined with each other to form a bond, are onesshown by the following formula: ##STR4## wherein each symbol has themeaning given above. Compounds shown by the formula (I) wherein L and Meach are hydrogen, are ones shown by the following formula: ##STR5##wherein each symbol has the meaning given above.

In the formula (I), an alkyl group shown by R¹ and R2 is one having 1 to4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl, etc.

The above mentioned general formula (I-B1) represents both (E)- and(Z)-isomers relative to the double bond at the 5-position of the2,4-oxazolidinedione ring.

With respect to the above general formula (I), in the case where R¹ andR² combine with each other to form a 5- or 6-membered heterocyclic ringoptionally containing N, examples of such compounds include thoserepresented by the following general formulas.

(1) R¹ and R² combine with each other to form a 5-membered heterocyclicring. ##STR6## (2) R¹ and R² combine with each other to form a6-membered heterocyclic ring. ##STR7## (3) R¹ and R 2 combine with eachother to form a 5-membered heterocyclic ring containing N. ##STR8## (4)R¹ and R² combine with each other to form a 6-membered heterocyclic ringcontaining N ##STR9## [wherein D stands for hydrogen or a lower alkylgroup, and other symbols have the meanings given above.]

Among the above-mentioned compounds (I-C1) to (I-C8), those representedby (I-C1), (I-C2), (I-C3) and (I-C6) are preferable.

In the above-mentioned general formula (I), as hydrocarbon residues inthe hydrocarbon residues which may be substituted shown by R, mention ismade of aliphatic hydrocarbon residues, alicyclic hydrocarbon residues,alicyclic-aliphatic hydrocarbon residues, aromatic aliphatic hydrocarbonresidues, aromatic hydrocarbon residues and aromaticheterocyclic-aliphatic hydrocarbons. As the aliphatic hydrocarbonresidues, mention is made of ones having 1 to 8 carbon atoms includingsaturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms asexemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, t.-pentyl, hexyl,isohexyl, heptyl and octyl, and unsaturated aliphatic hydrocarbonresidues having 2 to 8 carbon atoms as exemplified by ethenyl,1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl,1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl and1-octynyl. As the alicyclic hydrocarbon residues, mention is made ofones having 3 to 7 carbon atoms including saturated alicyclichydrocarbon residues having 3 to 7 carbon atoms as exemplified bycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, andunsaturated alicyclic hydrocarbon residues having 5 to 7 carbon atoms asexemplified by 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl,1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl,2-cycloheptenyl, 3-cycloheptenyl and 2,4-cycloheptadienyl. As thealicyclic-aliphatic hydrocarbon residues, mention is made of, amongthose formed by combination of the above-mentioned alicyclic hydrocarbongroups with aliphatic hydrocarbon residues, ones having 4 to 9 carbonatoms as exemplified by cyclopropylmethyl, cyclopropylethyl,cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl,3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl,3-cyclohexenylmethyl, cyclohexenylethyl, cyclohexylethyl,cyclohexylpropyl, cycloheptylmethyl and cycloheptylethyl. As thearomatic aliphatic hydrocarbon residues, mention is made of phenylalkylhaving 7 to 9 carbon atoms as exemplified by benzyl, phenethyl,1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 1-phenylpropyl, andnaphthylalkyl having 7 to 9 carbon atoms as exemplified byα-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl and β-naphthylethyl.As the aromatic hydrocarbon residues, mention is made of, for example,phenyl, naphthyl (α-naphthyl, β-naphthyl), among others. As the aromaticheterocyclic-aliphatic hydrocarbon residues, mention is made of thoseformed by combination of heterocyclic groups mentioned below with theabove-mentioned aliphatic hydrocarbon residues, which are exemplified asfollows.

In the above-mentioned general formula (I) as the heterocyclic groups inthe substituted heterocyclic groups which may be substituted shown by R,mention is made of, for example, 5- to 7-membered heterocyclic groupscontaining one sulfur atom, nitrogen atom or oxygen atom, 5- to6-membered heterocyclic groups containing 2 to 4 nitrogen atoms, and 5-to 6-membered heterocyclic groups containing 1 to 2 nitrogen atoms andone sulfur atom or oxygen atom. These heterocyclic groups are optionallycondensed with 6-membered ring containing one or two nitrogen atoms,benzene ring or 5-membered ring containing one sulfur atom. Examples ofthese heterocyclic groups include 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,isothiazolyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-triazol-3-yl,1,3,4-triazol-2-yl, 1,2,3-triazol-4-yl, tetrazol-5-yl,benzimidazol-2-yl, indol-3-yl, benzpyrazol-3-yl,1H-pyrrolo[2,3-b]pyrazin-6-yl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, and 1H-imidazo[4,5-b]pyrazin-2-yl, etc.

In the above-mentioned general formula (I) the hydrocarbon residue andheterocyclic residue shown by R optionally have 1 to 3 substituents atsubstitutable positions, respectively. As such substituents, mention ismade of aliphatic chain hydrocarbon group, alicyclic hydrocarbon group,aryl group, aromatic heterocyclic group, non-aromatic heterocyclicgroup, halogen atom, nitro group, optionally substituted amino group,optionally substituted acyl group, optionally substituted hydroxylgroup, optionally substituted thiol group and optionally esterifiedcarboxyl group. As the aliphatic chain hydrocarbon group, mention ismade of straight-chain or branched aliphatic hydrocarbon groups having 1to 15 carbon atoms, for example, alkyl group, preferably alkyl grouphaving 1 to 10 carbon atoms, alkenyl group, preferably alkenyl grouphaving 2 to 10 carbon atoms, and alkynyl group, preferably alkynyl grouphaving 2 to 10 carbon atoms.

Preferable examples of the alkyl group include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, tert-pentyl, 1-ethyl propyl, hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl.Preferable examples of the alkenyl group include vinyl, allyl,isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl,2-hexenyl, 3-hexenyl and 5-hexenyl. Preferable examples of the alkynylgroup include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. As the alicyclichydrocarbon group, mention is made of saturated or unsaturated alicyclichydrocarbon groups having 3 to 12 carbon atoms, for example, cycloalkylgroup, cycloalkenyl group and cycloalkadienyl group. Preferable examplesof cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.1]nonyl,bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl, etc.Preferable examples of cycloalkenyl group include 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl. Aspreferable examples of cycloalkadienyl group include2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl and2,5-cyclohexadien-1-yl. The said aryl group means monocyclic orcondensed polycyclic aromatic hydrocarbon groups. Preferable examples ofthe aryl group include ones having 6 to 14 carbon atoms such as phenyl,naphthyl, anthryl, phenanthryl and acenaphthylenyl. Among them, phenyl1-naphthyl and 2-naphthyl are preferable.

Preferable examples of the aromatic heterocyclic group include aromaticmonocyclic heterocyclic groups such as furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl and triazinyl; and aromatic condensedheterocyclic groups such as benzofuranyl, isobenzofuranyl,benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzoimidazolyl,benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2- a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl and 1,2,4-triazolo[4,3-b]pyridazinyl, etc.

Preferable examples of the non-aromatic heterocyclic group includeoxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, pyrrolidino, piperidino, morpholino and piperazinyl.Examples of the halogen include fluorine, chlorine, bromine and iodine.Among them, fluorine and chlorine are especially preferable. Theoptionally substituted includes unsubstituted amino group andsubstituted amino group. As the substituted amino group, mention is madeof amino group (--NH₂) on which one or two of alkyl having 1 to 10carbon atoms, alkenyl having 1 to 10 carbon atoms, aromatic group oracyl group having 2 to 10 carbon atoms (e.g. methylamino, dimethylamino,ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino,phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, andbenzoylamino etc.) is substituted. The optionally substituted acyl groupincludes unsubstituted acyl group and substituted acyl groups. As theunsubstituted acyl group, mention is made of formyl and those formed bycondensation of (C₁ -C₁₀)alkyl, (C₁ -C₁₀)alkenyl or (C₆ -C₁₂)aromaticgroup with carbonyl group (e.g. acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl,cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, cycloheptanoyl, crotonyl,2-cyclohexenecarbonyl, benzoyl and nicotinoyl). The substituted acylgroup includes acyl groups mentioned above in connection withunsubstituted acyl group which have substituent(s) such as an alkylhaving 1 to 3 carbon atoms, an alkoxy having 1 to 3 carbon atoms,halogen (e.g. chlorine, bromine etc.), nitro hydroxy, amino etc. Theoptionally substituted hydroxyl group includes unsubstituted hydroxylgroup and substituted hydroxyl groups. As the substituted hydroxylgroup, mention is made of such ones as having, on this hydroxyl group, asuitable substituent, especially the one employable as ahydroxyl-protecting group, as exemplified by besides alkoxy, alkenyloxy,aralkyloxy, acyloxy and aryloxy. Preferable examples of the alkoxyinclude ones having 1 to 10 carbon atoms (e.g. methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy,isopentoxy, neopentoxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy,cyclopentoxy and cyclohexyloxy). As alkenyloxy, mention is made of oneshaving 1 to 10 carbon atoms oil including, for example, allyloxy,crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy and2-cyclohexenylmethoxy, and, as aralkyloxy, mention is made of, forexample, phenyl-(C₁ -C₄)alkyloxy (e.g. benzyloxy and phenethyloxy).Preferable examples of acyloxy include alkanoyloxy having 2 to 4 carbonatoms (e.g. acetyloxy, propionyloxy, n-butyryloxy and iso-butyryloxy).As aryloxy, mention is made of 4-chlorophenoxy, among others.

As the optionally substituted thiol group, mention is made of, besidesthiol group, such ones as having, on this thiol group, a suitablesubstituent, especially the one employable as a thiol-protecting group,as exemplified by alkylthio, aralkylthio and acylthio. Preferableexamples of the alkylthio include alkylthio having 1 to 10 carbon atoms(e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio,neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio,cyclopentylthio and cyclohexylthio. As aralkylthio, mention is made of,for example, phenyl-(C₁ -C₄)alkylthio (e.g. benzylthio andphenethylthio). Preferable examples of acylthio include alkanoylthiohaving 2 to 4 carbon atoms (e.g. acetylthio, propionylthio,n-butyrylthio and iso-butyrylthio). As the optionally esterifiedcarboxyl group, mention is made of, for example, alkoxycarbonyl (e.g.ones having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl and butoxycarbonyl), aralkyloxycarbonyl (e.g.benzyloxycarbonyl) and aryloxycarbonyl (e.g. phenoxycarbonyl andp-tolyloxycarbonyl).

In the above-mentioned general formula (I) substituents on thehydrocarbon residue and heterocyclic group shown by R may, when they arealicyclic hydrocarbon group, aryl group, aromatic heterocyclic group ornon-aromatic heterocyclic group, have one or more, preferably 1 to 3, ofsuitable substituents respectively. Examples of these substituentsinclude lower alkyl groups having 1 to 4 carbon atoms, lower alkenylgroups having 2 to 5 carbon atoms, lower alkynyl groups having 2 to 5carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, aryl groups(e.g. phenyl, naphthyl, etc.), aromatic heterocyclic groups (e.g.thienyl, funyl, pyridyl, oxazolyl, thiazolyl, etc.), non-aromaticheterocyclic groups, (e.g. tetrahydrofuryl, morpholino, piperidino,pyrrolidino, piperazino, etc.), aralkyl groups having 7 to 9 carbonatoms, amino group, n-mono-(C₁ -C₄)alkyl amino groups, N,N-di(C_(l)-C₄)alkyl amino groups, amidino groups, acyl group having 2 to 5 carbonatoms, carbamoyl group, N-mono-(C₁ -C₄)alkyl carbamoyl groups, N,N-di(C₁-C₄)alkyl carbamoyl group, sulfamoyl group, N-mono(C₁ -C₄)alkylsulfamoyl groups, N,N-di(C₁ -C₄)alkylsulfamoyl groups, carboxyl group,lower alkoxycarbonyl groups having 2 to 5 carbon atoms, hydroxyl group,lower alkoxy groups having 1 to 4 carbon atoms, lower alkenyloxy groupshaving 2 to 5 carbon atoms, cycloalkyloxy groups having 3 to 7 carbonatoms, aralkyloxy groups having 7 to 9 carbon atoms, aryloxy groups(e.g. phenyloxy, naphthyloxy, etc.), mercapto group, lower alkylthiogroups having 1 to 4 carbon atom, aralkylthio groups having 7 to 9carbon atoms, arylthio groups (e.g. phenylthio, naphthylthio, etc.),sulfo group, cyano group, azide group, nitro group, nitroso group andhalogen (e.g. fluorine, chlorine, bromine, iodine).

In the above formula (I), when each m and n is 0, carbon substituted byR¹ is directly bonded to R; when m is 0 and n is 1 or 2, R is directlybonded to --(CH₂)_(n) --; and when m is 1 and n is 0, Y is directlybonded to the carbon substituted by R¹.

Y is --CO--, --CH(OH)-- or --N(R³)--, preferably --CH(OH)-- or--N(R³)--. The alkyl group shown by R³ is one having 1 to 4 carbonatoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, etc.As the substituent of the alkyl, a halogen atom (e.g. fluorine,chlorine, bromine, iodine), an alkoxy group having 1 to 4 carbon atoms,(e.g. methoxy, ethoxy, propoxy, n-butoxy, t-butoxy, etc.), hydroxyl,nitro, an acyl group having 1 to 4 carbon atoms (e.g. formyl, acetyl,propionyl, etc.) are mentioned.

The bivalent straight or branched hydrocarbon chain residue shown by Aincludes saturated one [i.e. --CH₂ --, --(CH₂)₂ --, --CH(CH₃)--,--(CH₂)₃ --, --CH(C₂ H₅)--, --(CH₂)₄, --(CH₂)₅, --(CH₂)₆ and --(CH₂)₇--] and unsaturated one (e.g. --CH═CH--, --C(CH₃)═CH--, --CH═CH--CH₂ --,--C(C₂ H₅)═CH--, --CH₂ --CH═CH--CH₂ --, --CH₂ --CH₂ --CH═CH--CH₂ --,--CH═CH--CH═CH--CH₂ --, --CH═CH--CH═CH--CH═CH--CH₂ --.

In the formula (I-C8), the alkyl group shown by D is one having 1 to 4carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl.

As salts of the compound (I) of this invention, pharmaceuticallyacceptable ones are preferable, as exemplified by salts with aninorganic base, salts with an organic base, salts with an inorganicacid, salts with an organic acid, and salts with an basic or acidicamino acid. Preferable examples of salts with an inorganic base includealkali metal salts such as sodium salts and potassium salts; alkalineearth metal salts such as calcium salts and magnesium salts; andaluminum salts, ammonium salts or the like. Preferable examples of saltswith an organic base include those with, for example, trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine and N,N'-dibenzylethylenediamine.Preferable examples of salts with an inorganic acid include those with,for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid or phosphoric acid. Preferable examples of salts with an organicacid include those with, for example, formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid and p-toluenesulfonic acid. Preferable examples ofsalts with a basic amino acid include those with, for example, arginine,lysine and ornithine, and, preferable examples of salts with an acidicamino acid include those with, for example, aspartic acid and glutamicacid. Among them, sodium salt or potassium salt is more preferable.

The compound (I) or its pharmaceutically acceptable salts of the presentinvention possess an action of lowering blood sugar with low toxicity,which can be used as such or in a composition with, for example, a perse known pharmacologically acceptable carrier, excipient and filler as atherapeutic agent of diabetes in mammals including man. Compound (I) orpharmaceutically acceptable salt thereof of the present invention alsoexhibits improving activity of insulin resistance and can also be usedas a hypotensor.

The compound (I) of this invention is low in toxicity. For example, oraladministration of the compound of Example 18 at a dose of 15 mg/kg/dayfor 4 days to mice caused no change in body weight and liver weight incomparison with the control group. And, oral administration of thecompound produced in Example 18 at a dose of 100 mg/kg orintraperitoneal administration at a dose of 50 mg/kg killed no testanimals.

The administration is usually performed orally in the form of, forexample, tablets, capsules (including soft capsules and microcapsules),powders and granules, and, depending on cases, non-orally in the formof, for example, injections, suppositories and pellets. The dosage foradults in the case of oral administration ranges from 0.05 to 10 mg/kgper day, desirably once to three times a day.

The compound (I) of this invention, mixed with pharmaceuticallyacceptable carriers, can be administered orally or non-orally in theform of solid preparations such as tablets, capsules, granules andpowders; or in the form of liquid preparations such as syrups andinjections.

As pharmaceutically acceptable carriers, use is made of conventionalorganic or inorganic carriers for pharmaceutical preparations, morespecifically, for example, excipients, lubricants, binders anddisintegrators for solid preparations; and solvents, solubilizers,suspending agents, isotonizers, buffering agents and local anestheticagents. And, upon necessity, such additives as antiseptics,anti-oxidants, colorants and sweeteners are further used. Preferableexamples of excipients include lactose, sucrose, D-mannitol, starch,crystalline cellulose and light silicon dioxide. Preferable examples oflubricants include magnesium stearate, calcium stearate, talc andcolloid silica. Preferable examples of binders include crystallinecellulose, sugar, D-mannitol, dextrin, hydroxypropyl cellulose,hydroxypropyl methyl cellulose and polyvinyl pyrrolidone. Preferableexamples of disintegrators include starch, carboxymethyl cellulose,carboxymethyl cellulose calcium, crosscarmelose sodium and carboxymethylstarch sodium. Preferable examples of solvents include distilled waterfor injection, alcohol, propylene glycol, macrogol, sesame oil and cornoil. Preferable examples of solubilizers include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodiumcitrate. Preferable examples of suspending agents include surfactantssuch as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionate, lecithin, benzalkonium chloride, benzethonium chloride,glycerin monostearate; and hydrophilic polymers such as polyvinylalcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose andhydroxypropylcellulose. Preferable examples of isotonizers includesodium chloride, glycerin and D-mannitol. Preferable examples ofbuffering agents include buffer solutions of phosphates, acetates,carbonates and citrates. Preferable examples of local anesthetic agentsinclude benzyl alcohol. Preferable examples of antiseptics includeparaoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethylalcohol, dehydroacetic acid and sorbic acid. Preferable examples ofanti-oxidants include sulfites and ascorbic acid.

The following is the description on the method of producing the compound(I) of this invention. ##STR10## [wherein each symbol has the samemeaning as defined above.]

The compound (I-B1) can be produced by condensation of the compound (II)with 2,4-oxazolidinedione. This reaction is conducted in a solvent inthe presence of a base. As the solvent, mention is made of alcohols suchas methanol, ethanol, propanol, isopropanol and 2-methoxyethanol;aromatic hydrocarbons such as benzene, toluene and xylene; ethers suchas ethyl ether, isopropyl ether, dioxane and tetrahydrofuran;N,N-dimethylformamide, dimethyl sulfoxide and acetic acid. As the base,use is made of sodium alkoxide (e.g. sodium methoxide, sodium ethoxide,etc.), potassium carbonate, sodium carbonate, sodium hydride, sodiumacetate or a secondary amine such as piperidine, piperazine,pyrrolidine, morpholine, diethylamine, diisopropylamine, among others.The amount of 2,4-oxazolidinedione to be used ranges from 1 to 10 molarequivalents, preferably 1 to 5 molar equivalents, relative to thecompound (II). The amount of the base to be used ranges from 0.01 to 5molar equivalents, preferably 0.05 to 2 molar equivalents, relative tothe compound (II). This reaction is conducted at temperatures rangingfrom 0 to 150° C., preferably from 20 to 100° C., over a period rangingfrom 0.5 to 30 hours.

The compound (I-B1) to be produced by the above method is, in someinstances, obtained as a mixture of (E)-compound and (Z)-compound,relative to the double bond at 5-position of the 2,4-oxazolidinedionering. ##STR11## [wherein Z is hydrogen, a lower alkyl group or anaralkyl group, and other symbols have the meanings given above.]

In the above-mentioned general formula (III), as the lower alkyl groupshown by Z, mention is made of alkyl havaing 1 to 4 carbon atoms (e.g.methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andtert-butyl). The aralkyl group shown by Z means an alkyl group havingaryl group as the substituent. Examples of the aryl group include phenyland naphthyl, which may optionally be substituted with theafore-mentioned alkyl groups having 1 to 4 carbon atoms, halogen atoms(e.g. fluorine, chlorine, bromine, iodine), hydroxyl group and nitrogroup. As the alkyl moiety of the aralkyl group, alkyls having 1 to 4carbon atoms such as methyl, ethyl, propyl, etc. are mentioned.Preferable examples of the aralkyl group include benzyl, phenethyl,3-phenylpropyl, (1-naphthyl)methyl and (2-naphthyl)methyl, etc. Amongthem, benzyl and phenethyl are preferable.

An alkali metal salt of the compound (I-B2) can be produced by allowinga compound (III) to react with an alkali metal cyanate such as potassiumcyanate or sodium cyanate. Then, the alkali metal salt is treated withan acid to produce the compound (I-B2). The reaction of the compound(III) with the alkali metal cyanate is conducted in an adequate solvent.As the solvent, use is generally made of alcohols such as methanol,ethanol, propanol, isopropanol, 2-methoxyethanol and butanol,N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile or a suitablemixture of them. The amount of the alkali metal cyanate to be usedranges from 1 to 10 molar equivalents, preferably 1 to 5 molarequivalents. The reaction temperature ranges from 0 to 150° C.,preferably from 10 to 120° C., and the reaction time ranges from 0.5 to50 hours. The alkali metal salt of the compound (I-B2) thus obtained istreated with an acid by a conventional means to produce the compound(I-B2). This acid treatment is conducted in the presence or absence of asuitable solvent. Examples of the solvent include alcohols such asmethanol, ethanol, propanol, isopropanol, 2-methoxyethanol and butanol;aromatic hydrocarbons such as benzene, toluene and xylene; ethers suchas ethyl ether, isopropyl ether, dioxane and tetrahydrofuran;halogenated hydrocarbons such as chloroform, dichloromethane and1,1,2,2-tetrachloroethane; ethyl acetate, acetonitrile or a mixture ofthem. As the acid, use is preferably made of an excess amount of aninorganic acid such as hydrochloric acid, sulfuric acid, nitric acid andhydrobromic acid, while an organic acid such as acetic acid, citricacid, tartaric acid or the like can also be used.

Thus obtained 2,4-oxazolidinedione derivative (I-B2) can be isolated andpurified by a known isolating and purifying means such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phasic transfer, chromatography orthe like. ##STR12## [wherein A¹ is a saturated bivalent straight orbranched hydrocarbon chain residue having 1 to 7 carbon atoms, and othersymbols have the meanings given above.]

The saturated bivalent straight or branched hydrocarbon chain residuehaving 1 to 7 carbon atom shown by A is the saturated one given as thedefinition of A.

By subjecting the compound (I-B1) to reduction, the compound (I-B2a) canbe produced. This reduction is conducted, in accordance with aconventional method, in the presence of a catalyst under hydrogenatmosphere of 1 to 150 atmospheric pressure. As the solvent, mention ismade of alcohols such as methanol, ethanol, propanol, isopropanol and2-methoxyethanol, aromatic hydrocarbons such as benzene, toluene andxylene, ethers such as ethyl ether, isopropyl ether, dioxane andtetrahydrofuran, halogenated hydrocarbons such as chloroformdichloromethane and 1,1,2,2-tetrachloroethane, ethyl acetate, aceticacid, N,N-dimethylformamide or a suitable mixture of them. Examples ofpreferable catalysts include metals such as nickel compounds andtransition metals such as palladium, platinum and rhodium. Reactiontemperatures range from 0 to 100° C., preferable from 10 to 80° C.Reaction time ranges from 0.5 to 50 hours. The 2,4-oxazolidinedionederivative (I-B2a) thus obtained can be isolated and purified by a knownrefining means such as concentration, concentration under reducedpressure, solvent extraction, crystallization, recrystallization, phasictransfer and chromatography. ##STR13## [wherein B stands for loweralkoxy, lower alkylthio or lower acyloxy; and other symbols are of thesame meaning as defined above].

As the lower alkoxy, lower alkylthio and lower acyloxy, respectivelyshown by B, mention is made of, for example, ones having 1 to 4 carbonatoms such as methoxy, ethoxy, propoxy, isopropoxy and butoxy; oneshaving 1 to 4 carbon atoms such as methyl thio, ethylthio, propylthio,i-propylthio and butylthio; ones having 1 to 4 carbon atoms such asacetyloxy and propionyloxy, respectively. Depending cases, two B's maybe combined to each other to form, for example, ethylenedioxy,propylenedioxy or dithiotrimethylene. In other words, --CH(B)₂ of theformula (IV) means a protected aldehyde group.

The compound (IV) is condensed with 2,4-oxazolidinedione to produce acompound (I-B1). This condensation reaction is conducted substantiallythe same manner as in the reaction of the compound (II) with2,4-oxazolidinedione in Method A. ##STR14## [wherein Q is a leavinggroup and other symbols are of the same meaning as defined above]

As the leaving group shown by Q, mention is made of a halogen (e.g.chlorine, bromine, iodine), methanesulfonyloxy, benzenesulfonyloxy andp-toluenesulfonyloxy.

The compound (V) is condensed with the compound (VI) to produce acompound (I-DI). This reaction is conducted, in accordance with aconventional method, in an adequate solvent in the presence of a base.Examples of the solvent include aromatic hydrocarbon such as benzene,toluene and xylene; ethers such as dioxane, tetrahydrofuran anddimethoxyethane; ketones such as acetone and 2-butanone;N,N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane,1,2-dichloroethane, 1,1,2,2-tetrachloroethane; and a suitable mixture ofthese solvents. As the base, mention is made of alkali metal salt suchas sodium hydroxide, potassium hydroxide, potassium carbonate and sodiumhydrogencarbonate; amines such as pyridine, triethylamine,N,N-dimethylaniline; metal hydroxide such as sodium hydroxide andpotassium hydroxide; sodium ethoxide, sodium methoxide and potassiumt-butoxide, among others. The amount of these bases to be used ispreferably in a range of from about 1 to 5 mol. relative to the compound(V). This reaction is conducted usually at temperatures ranging from-50° C. to 150° C., preferably from about -10° C. to 100° C. Thereaction time ranges from 0.5 to 30 hours.

The starting compound of Method A can for example be prepared by MethodF. ##STR15## [wherein R⁴ and R⁵ independently stand for a lower alkylgroup; R⁶ stands for hydrogen or a lower alkyl group; q denotes 0, 1 or2; and other symbols are of the same meaning as defined above].

Examples of the lower alkyl groups shown by R⁴, R⁵ and R⁶ include oneshaving 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl andbutyl.

In this method, first, a formyl or a acyl derivative (VII) is allowed toreact with a phosphonoacetic acid derivative or a ω-phosphonocarboxylicacid derivative (VIII) to produce an unsaturated ester derivative (IX).The reaction of (VII) with (VIII) is conducted, in accordance with aconventional method, in an adequate solvent in the presence of a base.Examples of the solvent include aromatic hydrocarbon such as benzene,toluene and xylene; ethers such as dioxane, tetrahydrofuran anddimethoxyethane; alcohols such as methanol, ethanol and propanol;N,N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane,1,2,dichloroethane and 1,1,2,2-tetrachloroethane, as well as a suitablemixture of them. Examples of the base include alkali metal salts such assodium hydroxide, potassium hydroxide, potassium carbonate, sodiumcarbonate and sodium hydrogencarbonate; amines such as pyridine,triethylamine and N,N-dimethyl aniline; metal hydrides such as sodiumhydride and potassium hydride; sodium ethoxide, sodium methoxide andpotassium t-butoxide. The amount of these bases to be employed ranges,preferably, from about 1 to about 5 mol. relative to the compound(VIII). The amount of the compound (VIII) to be used ranges from 1 to 5mol., preferably from 1 to 3 mol., relative to the compound (VII). Thisreaction is conducted generally at temperatures ranging from -50° C. to150° C., preferably from about -10° C. to 100° C. The reaction timeranges from 0.5 to 30 hours.

Then, the compound (IX) is subjected to reduction to produce an alcoholderivative (X). This reduction reaction can be conducted by a per seknown method, for example, reduction with a metal hydride, reductionwith a metal hydride complex, and reduction with diborane and asubstituted borane. In other words, this reaction can be conducted bytreating the compound (IX) with a reducing agent. Examples of thereducing agent include alkali metal borohydrides (e.g. sodiumborohydride and lithium borohydride); metal hydride complex such aslithium aluminum hydride; and diborane, and use of diisobutyl aluminumhydride serves to conduct the reaction advantageously. This reaction isconducted in an organic solvent inert to the reaction. Examples of thesolvent include aromatic hydrocarbons such as benzene, toluene andxylene; halogenated hydrocarbons such as chloroform, carbontetrachloride, dichloromethane, 1,2-dichloroethane and1,1,2,2-tetrachloroethane; ethers such as diethyl ether, tetrahydrofuranand dioxane; alcohols such as methanol, ethanol, propanol, isopropanoland 2-methoxyethanol; amides such as N,N-dimethylformamide; or asuitable mixture of them, and, from among these solvents, a suitable oneis selectively employed depending on kinds of the reducing agent. Thereaction temperatures ranges from -20° C. to 150° C., especiallypreferably from 0° C. to 100° C., and the reaction time ranges fromabout 1 to 24 hours.

Then, the compound (X) is subjected to oxidation to produce anunsaturated aldehyde derivative (II-1). This oxidation reaction can beconducted by a per se known method, for example, oxidation withmanganese dioxide, oxidation with chromic acid, oxidation with dimethylsulfoxide, or the like. In other words, this reaction is conducted byprocessing the compound (X) with an oxidizing agent. As the oxidizingagent, use is made of manganese dioxide or chromic anhydride, and use ofthe former is preferable to conduct the reaction more advantageously.This reaction is conducted in an organic solvent inert to the reaction.As the solvent, use is made of, for example, aromatic hydrocarbons suchas benzene, toluene or xylene, halogenated hydrocarbons such aschloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane or1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuranor dioxane, dimethyl sulfoxide or a suitable mixture solvent thereof,and, from among these solvents, a suitable one is selectively employeddepending of kinds of the oxidizing agent. The reaction temperaturesrange from -20° C. to 150° C., especially those ranging from 0° C. to100° C. are preferable, and the reaction time ranges from about 1 to 24hours.

Then, the compound (II-1) is subjected to reduction reaction to producethe compound (II-2). This reduction reaction is conducted in the samemanner as Method C.

The aldehyde derivative (II-1), (II-2) thus obtained can be isolated andpurified by means of a conventional refining process, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phasic transfer, chromatography orthe like.

The compound (VII), which is the starting compound in Method F, can besynthesized in accordance with any method described in, for example,Chemical & Pharmaceutical Bulletin, Vol.39, p.1440 (1990), JPAH4(1992)-225978, JPA S61(1986)-85372, JPA S61(1986)-271287, JPAS63(1988)-139182, JPA H3(1991)-170478, WO9119496-A1, EP-428312-A, JPAH1(1989)-299289 and JPA S63(1988)-230689.

The pyridine aldehyde derivatives (VII-1) can for example be prepared byMethod G. ##STR16## [wherein Q' is a halogen atom, and other symbolshave the meaning given above.]

As the halogen atom shown by Q', chlorine, bromine, iodine may bementioned.

In this method, firstly, 2-chloro-5-nitropyridine is allowed to reactwith an alcohol derivative to produce the compound (XII). The reactionof 2-chloro-5-nitropyridine with the compound (XI) is conducted in asuitable solvent in the presence of a base in accordance with aconventional method. As the solvent, mention is made of, for example,aromatic hydrocarbons such as benzene, toluene or xylene, ethers such asdioxane, tetrahydrofuran or dimethoxyethane, N,N-dimethylformamide,dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane,1,1,2,2-tetrachloroethane and a suitable mixture solvent of them. As thebase, mention is made of, alkali metal salts such as sodium hydroxide,potassium hydroxide, potassium carbonate, sodium carbonate or sodiumhydrogencarbonate; amines such as pyridine, triethylamine orN,N-dimethylaniline; metal hydrides such as sodium hydride or potassiumhydride; sodium ethoxide, sodium methoxide and potassium t-butoxide. Theamount of these bases to be used is preferably in the range from 1 toabout 5 mol. relative to the compound (XI). This reaction is conductedusually at temperatures ranging from -50° C. to 150° C., preferable fromabout -10° C. to 100° C. The reaction time ranges from 0.5 to 30 hours.

Then, the compound (XII) is subjected to reduction to produce an aminederivative (XIII). While the reduction reaction can be conducted by aper se known method, catalytic reduction using a metal catalyst servesto perform the reduction more advantageously. This catalytic reductionis conducted, in accordance with a conventional method, in the presenceof a catalyst in hydrogen atmosphere of 1 to 150 atmospheric pressure.Examples of the solvent include alcohols such as methanol, ethanol,propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons suchas benzene, toluene and xylene; ethers such as ethyl ether, isopropylether, dioxane and tetrahydrofuran; halogenated hydrocarbons such aschloroform, dichloromethane and 1,1,2,2-tetrachloroethane; ethylacetate, acetic acid, N,N-dimethylformamide or a suitable mixturesolvent of them. Use of, for example, a metal such as a nickel compound,a transition metal catalyst such as palladium, platinum or rhodium, asthe catalyst serves to perform the reaction advantageously. The reactiontemperature ranges from 0 to 100° C., preferably from 10 to 80° C., andthe reaction time ranges from 0.5 to 50 hours.

Then, the compound (XIII) is subjected to the per se known the Sandmeyerreaction to produce a halogen derivative (XIV). In this reaction,firstly, the compound (XIII) is diazotized by adding dropwise thereto anaqueous solution of sodium nitrite in a solvent in the presence ofhydrochloric acid, hydrobromic acid or hydroiodic acid, which was thenallowed to react with an aqueous solution of sodium halogenate orpotassium halogenate, to thereby produce the compound (XIV). As thesolvent, use is made of alcohols such as methanol, ethanol, propanol,isopropanol and 2-methoxyethanol; ethers such as acetone, 2-butanone,dioxane and tetrahydrofuran; or a suitable mixture solvent of them. Thereaction temperature ranges from -50° C. to 100° C., preferably from -20to 60° C. The reaction time ranges from 0.5 to 50 hours.

Then, the compound (XIV) is processed with, for example, butyl lithium,sec.-butyl lithium, tert.-butyl lithium, methyl lithium, phenyl lithiumor phenyl magnesium bromide, which is then allowed to react withN,N-dimethylformamide (DMF) to produce a compound (VII-1).

A part of the intermediate compound (IX) in Method F can be producedalso by, for example, Method H. ##STR17## [wherein each symbol is of thesame meaning as defined above]

This reaction can be conducted in a suitable solvent in the presence ofa base. As the solvent, mention is made of aromatic hydrocarbons such asbenzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran anddimethoxyethane; alcohols such as methanol, ethanol and propanol; ethylacetate, acetonitrile, pyridine, N,N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane,1,1,2,2-tetrachloroethane, acetone, 2-butanone, and a suitable mixturesolvent of them. As the base, mention is made of an inorganic baseincluding, for example, alkali metal hydroxide (e.g. sodium hydroxideand potassium hydroxide), alkaline earth metal hydroxide (e.g. magnesiumhydroxide and calcium hydroxide), alkali metal carbonate (e.g. sodiumcarbonate and potassium carbonate), alkaline earth metal carbonate (e.g.magnesium carbonate and calcium carbonate), alkali metalhydrogencarbonate (e.g. sodium hydrogencarbonate and potassiumhydrogencarbonate) and alkali metal acetate (e.g. sodium acetate andpotassium acetate); and an organic base including trialkylamine (e.g.trimethylamine and triethylamine), picoline, N-methylpyrrolidine,N-methylmorpholine, 1,5-diazabicyclo [4,3,0] non-5-en, 1,4-diazabicyclo[2,2,2] non-5-ene and 1,8-diazabicyclo [5,4,0]-7-undecene. The amount ofthese bases to be used ranges preferably from about 1 to about 5 mol.relative to the compound (XV). This reaction is conducted usually attemperatures ranging from -20° C. to 150° C. preferably from about -10°C. to 100° C.

Methods of synthesizing the starting compound (XV) in Method H aredescribed in, for example, Chemical & Pharmaceutical Bulletin, 30,p.3563 (1982), Chemical & Pharmaceutical Bulletin, 30, p.3580 (1982),Chemical & Pharmaceutical Bulletin, 32, p.2267 (1984),Arzneimittel-Forschung/Drug Research 40, p.37 (1990), Journal ofMedicinal Chemistry, 35 p.2617 (1992), JPA S61(1986)-267580, JPAS61(1986)-286376, JPA S61(1986)-85372, JPA H2(1990)-31079 and JPAS62(1987)-5981.

The compound (III) used in Method B is produced by, for example, MethodI. ##STR18## [wherein A² is a bond or bivalent straight or branchedhydrocarbon chain residue having 1 to 5 carbon atoms; A³ is a bond or abivalent saturated straight or branched hydrocarbon chain residue having1 to 5 carbon atoms, and the other symbols is of the same meaning asdefined above]

The bivalent straight or branched hydrocarbon chain residue shown by A²is the one having 1 to 5 carbon atoms among the bivalent straight orbranched hydrocarbon chain residue shown by A, and the bivalentsaturated straight or branched hydrocarbon residue shown by A³ is thesaturated one among the bivalent straight or branched hydrocarbon chainresidue shown by A².

In this method, firstly, the compound (II-3) is condensed with pyruvicacid to produce a compound (XVI). Condensation reaction of the compound(II-3) with pyruvic acid is conducted in a mixture of alcohols and waterusing the same base as in the reaction of the compound (II) with2,4-oxazolidinedione in Method A. Then, the compound (XVI) is subjectedto esterification to produce a compound (XVII). This esterificationreaction can be conducted by a per se known method, for example, amethod which comprises allowing the compound (XVII) to react directlywith alcohol (R⁴ OH) in the presence of an acid to cause esterification,or a method which comprises a reactive derivative of the compound (XVI),for example, acid anhydride, acid halide (acid chloride, acid bromide),imidazolide or a mixed acid anhydride (e.g. anhydride with methylcarbonate, anhydride with ethyl carbonate, anhydride with isobutylcarbonate or the like) to adequately react with alcohol (R⁴ OH). Then,the compound (XVII) is subjected to catalytic reduction to produce acompound (XVIII). This catalytic reduction is conducted in substantiallythe same manner as in Method C. Then, the compound (XVIII) is subjectedto reduction to produce a compound (III-1). This reduction reaction canbe conducted by a per se known method. For example, reduction by using ametal hydride, reduction by using a metal hydride complex compound,reduction by using diborane or a substituted diborane, catalytichydrogenation or the like are mentioned. In other words, this reactionis conducted by processing the compound (XVIII) with a reducing agent.As the reducing agent, mention is made of alkali metal borohydride (e.g.sodium borohydride, lithium borohydride, etc.), a metal hydride complexcompound such as lithium aluminum hydride, metal hydride such as sodiumhydride, an organotin compound (triphenyltin hydride, etc.), metals andmetal salts including nickel compounds, zinc compounds or the like,transition metal catalysts including palladium, platinum, rhodium or thelike, to be used together with hydrogen, and diborane, among others.Above all, use of alkali metal borohydride (e.g. sodium borohydride,lithium borohydride, etc.) is advantageous. This reaction is conductedin an organic solvent which does not give undesirable influences uponthe reaction. Examples of the solvent include aromatic hydrocarbons suchas benzene, toluene and xylene; halogenated hydrocarbons such aschloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethaneand 1,1,2,2-tetrachloroethane; ethers such as diethyl ether,tetrahydrofuran and dioxane; alcohols such as methanol, ethanol,propanol, isopropanol and 2-methoxyethanol; amides such asN,N-dimethylformamide; or a suitable mixture of these solvents. Fromamong them, a suitable one is selectively employed depending on types ofreducing agents. The reaction temperature ranges preferably, from -20°C. to 150° C., especially from 0° C. to 100° C. The reaction time rangesfrom about 1 to 24 hours.

The starting compound (IV) of Method D and the starting compound (II) ofMethod A can, for example, be prepared by Method J. ##STR19## [wherein lis an integer of from 1 to 6, and other symbols have the meaning givenabove.]

In this method, firstly, the compound (VII) is condensed with thecompound (XIX) to produce a compound go (IV-1). This condensationreaction is conducted in substantially the same manner as in thereaction of the compound (VII) with the compound (VIII) in Method F.Then, the compound (IV-1) is subjected to reduction reaction to give(IV-2). This reduction reaction is substantially the same manner as inthe catalytic reduction reaction of the compound (I-B1) in Method C. Thecompound (IV-2) can be led to an aldehyde derivative (II-4) bysubjecting the former to deprotection by processing with an acid in anaqueous solvent. As the aqueous solvent, mention is made of a mixture ofan alcohol such as methanol, ethanol and propanol; an ether such astetrahydrofuran and dioxane; acetonitrile, acetone, 2-butanone, aceticacid or the like, with water. As the acid, mention is made of, forexample, p-toluenesulfonic acid, besides, inorganic acid such ashydrochloric acid, sulfuric acid, nitric acid and hydrobromic acid.

A part of the compounds (II) and (IV) can be prepared by Method K.##STR20## [wherein w is --CH<_(B) ^(B) (B has the meaning shown above),and other symbols have the meaning shown above.] This reaction iscarried out by a similar manner to that in Method E.

A part of the compound produced by Method E can be subjected toreduction to give a compound (I-B2a2). ##STR21## (wherein each symbolhas the meaning given above.) This reaction is carried out by a similarmanner to that in reduction of Method I in which compound (XVIII) isintroduced to compound (III-1).

The compounds (II-2) and (II-4) can also be prepared by Method M.##STR22## (wherein each symbol has the meaning given above.)

The compound (XXII), which is produced by catalytic hydrogenation of thecompound (XI), can be converted to compound (XXIII). The reaction iscarried out by a similar manner to that in the reaction of Method F inwhich compound (IX) is introduced to compound (X). Compound (XXIII) canbe subjected to oxidation to give compounds (II-2) and (II-4).

This oxidation reaction is carried out by a known conventional mannersuch as Jones' oxidation using sulfuric acid-pyridine, Collins oxidationusing chromium oxide-pyridine complex, oxidation using pyridiniumchlorochromate (PCC), pyridinium dichromate (PDC), oxidation usingactivated dimethyl sulfoxide (DMSO), oxidation using oxoammonium salt,etc. It is preferable to use activated DMSO when the the startingcompound which is subjected to oxidation is optically active. Oxidationusing activated DMSO is carried out in the presence of DMSO and anelectrophilic reagent in a solvent. As the solvent, mention is made ofethers (e.g. ethyl ether, isopropyl ether, tetrahydrofuran, dioxane,etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.),N,N-dimethylformamide (DMF), halogenated hydrocarbons (e.g. chloroform,dichloromethane, etc.), pyridine and dimethyl sulfoxide. From thesesolvent, a proper solvent can be selected in view of the kind ofelectrophilic reagent used.

As the oxidation using DMSO, there are dicyclohexylcarbodiimide-method,acetic anhydride-method, phosphorous pentoxide-method, chlorine-method,sulfurtrioxide-pyridine-method, keteneimire-enamine-method,mercury-acetate (II)-method, etc. Among them, sulfurtrioxide-pyridine-method is advantageously used. Sulfurtrioxide-pyridine-method is carried out by using sulfurtrioxide-pyridine complex as an activator for DMSO in the presence oftriethylamine. This method can be carried out using an excess amount ofDMSO as a solvent. Trilthylamine and sulfur trioxide-pyridine complexeach are used in the range of 1 to 10 mol equivalent, preferably 2 to 5mol equivalent relative to one mole equivalent of compound (XXIII). Thereaction temperature is -70° C. to 80° C., preferably -20° C. to 40° C.The reaction time ranges usually from 0.5 to 10 hours.

The aldehyde derivatives (II-2), (II-4) thus obtained can be isolatedand purified by means of conventional refining process, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phasic transfer, chromatography orthe like.

The compounds (II-2) and (II-4) can be converted to compound (IV-2) byacetalization or dithioacetalization.

Among the compound (XXII), benzoxazole derivative 30 (XII-1) can beprepared by Method N. ##STR23## (wherein each symbol has the meaninggiven above)

This reaction is conducted in an organic solvent inert to the reaction.Examples of the solvent include aromatic hydrocarbons such as xylene,toluene, benzene, etc., ethers such as tetrahydrofuran, dioxane, etc.,halogenated hydrocarbons such as dichlorobenzene, chlorobenzene,methylenechloride, etc. While sole solvent may be used, a mixture of twoor more solvent may be used.

This reaction is usually carried out by heating a mixture of compound(XXIV) and (XXV) in a suitable solvent. The temperature is usually about30° C. to about 200° C., preferably about 50° C. to 180° C.

This reaction may be conducted in the presence of a dehydrating agent.As the dehydrating agent, phosphorous compound such as phosphoruspentoxide and phosphorus oxychloride are mentioned. The dehydratingagent is used in an amount of about 1 to 10 mole equivalent, preferablyabout 1 to 4 mole equivalent relative to the compound (XXIV). Whenphosphorus oxychloride is used, it can be used in an large excess amountas a solvent. When phosphorus pentoxide is used, addition ofhexamethyldisiloxane {[CH₃)₃ Si]₂ O} is advantageous to proceed thereaction. In this case, it is preferable to use hexamethyldisiloxane inan amount of about 2 to 4 mole equivalent relative to phosphoruspentoxide. The reaction time is usually about 1 to 30 hours, preferablyabout 1 to 10 hours.

The compound (I) of this invention possess excellent hypoglycemic andhypolipidemic activities.

EXPERIMENTAL EXAMPLE

Hypoglycemic and hypolipidemic actions in mice

A test compound mixed in a powdery feed (CE-2, Japan Clea) at a rate of0.005% was fed to KKA^(y) mice (9-14 week old) freely for 4 days. Duringthe period, the animals had free access to water. Blood was collectedfrom the orbital venous plexus. Using the plasma, glucose andtriglyceride were enzymatically determined quantitatively by usingIatrochem-GLU(A) and Iatro-MA701 TG kit (Iatron Inc.). The respectivevalues are percents reduction (%) found in drug-dosed groups from thecontrol group not receiving the test compound, which are shown in [Table1].

    [TABLE 1]                                                                     ______________________________________                                                      Hypoglycemic                                                                             Hypolipidemic                                        Compound      Action     Action                                               (Example No.) % reduction                                                                              % reduction                                          ______________________________________                                        18            43         41                                                   19            50         36                                                   23            39         33                                                   24            56         53                                                   26            42         32                                                   27            53         15                                                   29            61         83                                                   30            57         70                                                   32            63         60                                                   33            45         59                                                   34            43         51                                                   35            42         32                                                   36            56         48                                                   43            58         75                                                   52            54         82                                                   56            32         24                                                   60            54         77                                                   ______________________________________                                    

As stated above, 2,4-oxazolidinedione derivatives (I) of the presentinvention exhibit excellent hypoglycemic and hypolipidemic actions, andare pharmaceutically useful as therapeutic agents for diabetes,hyperlipemia and hypertension, for example.

EXAMPLE 1

A mixture of(E)-4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamaldehyde(1.20 g), 2,4-oxazolidinedione (0.525 g), piperidine (0.09 g) andethanol (20 ml) was heated for 5 hours under reflux. The reactionmixture was poured into water, which was acidified with 2N HCl, followedby extraction with ethyl acetate. The ethyl acetate layer was washedwith water, dried (MgSO₄) and, then, concentrated. The concentrate waspurified by means of a silica gel column chromatography. From thefractions eluted with chloroform-methanol (50:1) was obtained5-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamylidene]-2,4-oxazolidinedione(0.51 g, 34%). Recrystallization from dichloromethane-methanol gave paleyellow prisms, m.p.213-214° C.

EXAMPLE 2 TO EXAMPLE 7

In substantially the same manner as in Example 1, compounds shown in[Table 2] were obtained.

                                      TABLE 2                                     __________________________________________________________________________    1 #STR24##                                                                    Example                Yield                                                                            m.p.    Recrystallization                           No.  R                 (%)                                                                              (° C.)                                                                         solvent                                     __________________________________________________________________________         2 #STR25##        30 211-213 (decomposition)                                                               chloroform- methanol                        3                                                                                  3 #STR26##        26 227-228 chloroform- methanol                        4                                                                                  4 #STR27##        29 222-224 dichloromethane- methanol                   5                                                                                  5 #STR28##        31 206-207 dichloromethane- methanol                   6                                                                                  6 #STR29##        23 Note 1) 197-198                                                                       chloroform- methanol- hexane                7                                                                                  7 #STR30##        23 203-204 ethyl acetate- hexane                       __________________________________________________________________________     Note 1) 1/2 hydrate                                                      

EXAMPLE 8

In substantially the same manner as in Example 1,5-[3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]-2-propenylidene]-2,4-oxazolidinedionewas obtained. Recrystallization from ethanol-chloroform-isopropyl ethergave pale yellow crystals, m.p.204-205° C.

EXAMPLE 9

A mixture of2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-1,3-dioxane(2.0 g), 2,4-oxazolidinedione (0.99 g), piperidine (0.21 g) and aceticacid (50 ml) was heated for 24 hours under reflux. The reaction mixturewas concentrated under reduced pressure, to which was added ethylacetate. The ethyl acetate layer was washed with an aqueous solution ofsodium hydrogencarbonate, 2N HCl and water, successively, which was thendried (MgSO₄), followed by concentration. The concentrate was purifiedby means of a silica gel column chromatography. From the fractionseluted with chloroform-ethyl acetate (5:1),5-[4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butylidene]-2,4-oxazolidinedione(0.55 g, 26%) was obtained. Recrystallization from ethyl ether-methanolgave colorless needles, m.p.152-153° C.

EXAMPLE 10 TO EXAMPLE 13

In substantially the same manner as in Example 1, compounds shown in[Table 3] were obtained.

                                      TABLE 3                                     __________________________________________________________________________    8 #STR31##                                                                    Example                    Yield                                                                            m.p. Recrystallization                          No.  R                     (%)                                                                              (° C.)                                                                      solvent                                    __________________________________________________________________________    10                                                                                 9 #STR32##            33 198-200                                                                            dichloromethane methanol                   11                                                                                 0 #STR33##            31 195-197                                                                            dichloromethane methanol                   12                                                                                 1 #STR34##            42 201-203                                                                            methanol- ethyl acetate                    13                                                                                 2 #STR35##            26 244-245                                                                            chloroform- methanol                       __________________________________________________________________________

EXAMPLE 14

In substantially the same manner as in Example 1,(E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]acroleinwas allowed to react with 2,4-oxazolidinedione to give5-[3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]-2-propenylidene]-2,4-oxazolidinedione.The yield was 44%. Recrystallization from dichloromethane-methanol gavepale yellow needles, m.p.237-239° C.

EXAMPLE 15

In substantially the same manner as in Example 1,(E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadien-1-alwas allowed to react with 2,4-oxazolidinedione to give5-[5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadienylidene]-2,4-oxazolidinedione.The yield was 31%. Recrystallization from dichloromethane-methanol gaveyellow needles, m.p.209-211° C.

EXAMPLE 16

A mixture of5-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamylidene]-2,4-oxazolidinedione(0.29 g), palladium-carbon (10%, 0.1 g) and dioxane (50 ml) wassubjected to catalytic hydrogenation at room temperature underatmospheric pressure. The catalyst was filtered off, and the filtratewas concentrated under reduced pressure. The concentrate was purified bymeans of a silica gel column chromatography. From the fractions elutedwith chloroform-methanol (100:3) was obtained5-[3-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]phenyl]propyl]-2,4-oxazolidinedione(0.28 g, 96%). This product was recrystallized fromdichloromethane-methanol to give colorless prisms, m.p.149-150° C.

Elemental Analysis for C₂₅ H₂₆ N₂ O₅ : Calcd.: C, 69.11; H, 6.03; N,6.45 Found: C, 69.18; H, 6.01; N, 6.46

EXAMPLE 17 TO EXAMPLE 22

In substantially the same manner as in Example 16, compounds set forthin [Table 4] were obtained.

                                      TABLE 4                                     __________________________________________________________________________    3 #STR36##                                                                    Example                Yield                                                                            m.p. Recrystallization                              No.  R 22              (%)                                                                              (° C.)                                                                      solvent                                        __________________________________________________________________________    17                                                                                 4 #STR37##        87 143-144                                                                            dichloromethane- methanol                      18                                                                                 5 #STR38##        77 162-163                                                                            ethyl acetate- hexane                          19                                                                                 6 #STR39##        57 169-170                                                                            dichloromethane- methanol                      20                                                                                 7 #STR40##        59 153-154                                                                            dichloromethane- methanol                      21                                                                                 8 #STR41##        34 154-155                                                                            ethyl acetate- hexane-isopropyl ether          22                                                                                 9 #STR42##        89 127-128                                                                            ethyl acetate- hexane                          __________________________________________________________________________

EXAMPLE 23

In substantially the same manner as in Example 16,5-[3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]-2-propenylidene]-2,4-oxazolidinedionewas subjected to catalytic hydrogenation to give5-[3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]propyl]-2,4-oxazolidinedione.The product was recrystallized from chloroform-methanol-isopropyl etherto give colorless crystals, m.p.169-171° C.

Elemental Analysis for C₂₃ H₂₃ N₃ O₅.1/2H₂ O: Calcd.: C, 64.18; H, 5.62;N, 9.76 Found: C, 64.31; H, 5.70; N, 9.48

EXAMPLE 24

A mixture of ethyl2-hydroxy-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyrate(0.45 g), powdery potassium cyanate (0.24 g) and butanol (20 ml) washeated for 4 days under reflux. The solvent was distilled off underreduced pressure, and the residue was acidified with 2N HCl, followed byextraction with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and concentrated. The concentrate was purified bymeans of a silica gel column chromatography. From the fractions elutedwith chloroform-methanol (100:3) was obtained5-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]ethyl]-2,4-oxazolidinedione(0.28 g, 63%). The product was recrystallized fromdichloromethane-ethanol to give colorless prisms, m.p.193-194° C.

Elemental Analysis for C₂₃ H₂₂ N₂ O₅ : Calcd.: C, 67.97; H, 5.46; N,6.89 Found: C, 67.92; H, 5.61; N, 6.64

EXAMPLE 25

A mixture of5-[4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butylidene]-2,4-oxazolidinedione(0.38 g), palladium-carbon (10%, 0.2 g) and tetrahydrofuran (40 ml) wassubjected to catalytic hydrogenation at room temperature and 3 atom. Thecatalyst was filtered off, and the filtrate was concentrated underreduced pressure. The concentrate was purified by means of a silica gelcolumn chromatography. From the fractions eluted withchloroform-methanol (100:3) was obtained5-[4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyl]-2,4-oxazolidinedione(0.25 g, 65%). This product was recrystallized fromdichloromethane-methanol to give colorless prisms, m.p.136-137° C.

EXAMPLE 26 TO EXAMPLE 29

In substantially the same manner as in Example 16, compounds shown inTable 5 were obtained.

                                      TABLE 5                                     __________________________________________________________________________    0 #STR43##                                                                    Example                    Yield                                                                            m.p. Recrystallization                          No.  R                     (%)                                                                              (° C.)                                                                      solvent                                    __________________________________________________________________________    26                                                                                 1 #STR44##            65 168-169                                                                            dichloromethane- methanol                  27                                                                                 2 #STR45##            79 163-164                                                                            dichloromethane- methanol                  28                                                                                 3 #STR46##            73 138-139                                                                            dichloromethane- isopropyl ether           29                                                                                 4 #STR47##            52 157-158                                                                            ethyl acetate- hexane                      __________________________________________________________________________

EXAMPLE 30

In substantially the same manner as in Example 16, was obtained5-[3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]propyl]-2,4-oxazolidinedione.The yield was 80%. Recrystallization of this product fromdichloromethane-methanol gave colorless needles, m.p.184-185° C.

EXAMPLE 31

In substantially the same manner as in Example 16,5-[5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadienylidene]-2,4-oxazolidinedionewas subjected to catalytic hydrogenation to give5-[5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]pentyl]-2,4-oxazolidinedione.The yield was 77%. Recrystallization from dichloromethane-methanol gavecolorless needles, m.p.157-158° C.

EXAMPLE 32

In substantially the same manner as in Example 24,5-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-2,4-oxazolidinedionewas obtained. The yield was 35%. Recrystallization from ethylacetate-hexane gave colorless prisms, m.p.158-159° C.

EXAMPLE 33

To a solution of 5-[5-(4-hydroxyphenyl)pentyl]-2,4-oxazolidinedione (0.9g) in N,N-dimethylformamide (DMF) (40 ml) was added sodium hydride (60%in oil, 0.28 g). The mixture was stirred for 15 minutes at roomtemperature, to which was then added4-chloromethyl-5-methyl-2-phenyloxazole (0.85 g), and the mixture wasstirred for 2 hours at 70° C. The reaction mixture was poured intowater, acidified with 2N HCl, and subjected to extraction with ethylacetate. The ethyl acetate layer was washed with water, dried (MgSO₄),and then the solvent was distilled off. The oily residue was subjectedto a silica gel column chromatography. From the fractions eluted withethyl acetate-chloroform (1:5, v/v) was obtained5-[5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl]-2,4-oxazolidinedione(0.86 g, 58%). Recrystallization from dichloromethane-isopropyl ethergave colorless prisms, m.p.120-121° C.

EXAMPLE 34

In substantially the same manner as in Example 33, was obtained5-[4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]butyl]-2,4-oxazolidinedione.The yield was 32%. Recrystallization from dichloromethane-isopropylether gave colorless prisms, m.p.186-187° C.

EXAMPLE 35

A mixture of4-[4-[2-(1,3-dioxolan-2-yl)ethyl]phenoxyacetyl]-5-methyl-2-phenyloxazole(1.8 g), 2,4-oxazolidinedione (0.925 g), piperidine (0.12 g) and aceticacid (30 ml) was heated for 15 hours under reflux. The reaction mixturewas concentrated under reduced pressure. To the concentrate was added asaturated aqueous solution of sodium hydrogencarbonate, followed byextraction with chloroform. The chloroform layer was washed with water,dried (MgSO₄), followed by distilling off the solvent. The oily residuewas subjected to a silica gel column chromatography. From the fractionseluted with methanol-chloroform (1:30, v/v) was obtained5-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]phenyl]propylidene]-2,4-oxazolidinedione.This compound was dissolved in tetrahydrofuran (THF) (30 ml), to whichwas added palladium-carbon (5%, 0.3 g). The mixture was subjected tocatalytic hydrogenation. The catalyst was filtered off, and the filtratewas concentrated under reduced pressure. The oily residue was subjectedto a silica gel column chromatography. From the fractions eluted withethyl acetate-hexane (1:1, v/v),5-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]phenyl]propyl]-2,4-oxazolidinedione(0.32 g, 16%) was obtained as an oily product. NMR (δ ppm in CDCl₃):1.7-2.1(4H,m), 2.63(2H,t,J=7 Hz), 2.74(3H,s), 4.84(1H,dd,J=7&4.5 Hz),5.37(2H,s), 6.92(2H,d,J=9 Hz), 7.09(2H,d,J=9 Hz), 7.45-7.55(3H,m),7.95-8.1(3H,m).

EXAMPLE 36

To a solution of5-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]phenyl]propyl]-2,4-oxazolidinedione(0.2 g) in tetrahydrofuran (THF) (5 ml)-ethanol (5 ml) was added sodiumborohydride (0.03 g). The mixture was stirred for one hour at roomtemperature. To the reaction mixture were added 2N HCl and water,followed by extraction with ethyl acetate. The ethyl acetate layer waswashed with water and dried (MgSO₄), then the solvent was distilled off.The oily residue was subjected to a silica gel column chromatography.From the reactions eluted with chloroform-methanol (50:1, v/v) wasobtained5-[3-[4-[2-hydroxy-2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-phenyl]propyl]-2,4-oxazolidinedione(0.16 g, 80%). Recrystallization from dichloromethane-isopropyl ethergave colorless needles, m.p.146-147° C.

EXAMPLE 37-EXAMPLE 50

In substantially the same manner in Example 33, compounds shown in Table6 were obtained.

                                      TABLE 6                                     __________________________________________________________________________    5 #STR48##                                                                    Example                   Yield                                                                            m.p. Recrystallization                           No.  R                  k (%)                                                                              (° C.)                                                                      solvent                                     __________________________________________________________________________    37                                                                                 6 #STR49##         3 72 167-168                                                                            dichloromethane- methanol                   38                                                                                 7 #STR50##         3 66 148-149                                                                            dichloromethane isopropyl ether             39                                                                                 8 #STR51##         3 71 104-105                                                                            dichloromethane isopropyl ether             40                                                                                 9 #STR52##         3 23 177-178                                                                            dichloromethane- methanol                   41                                                                                 0 #STR53##         3 77 196-197                                                                            dichloromethane- methanol                   42                                                                                 1 #STR54##         3 75 137-138                                                                            dichloromethane- methanol                   43                                                                                 2 #STR55##         3 81 121-122                                                                            dichloromethane- methanol                   44                                                                                 3 #STR56##         3 80 155-156                                                                            dichloromethane- methanol                   45                                                                                 4 #STR57##         3 84 151-152                                                                            dichloromethane- methanol                   46                                                                                 5 #STR58##         3 72 oily 1) product                                                                    --                                          47                                                                                 7 #STR59##         5 79 159-160                                                                            dichloromethane- methanol                   48                                                                                 8 #STR60##         3 74 146-147                                                                            dichloromethane isopropyl ether             49                                                                                 9 #STR61##         3 70 148-149                                                                            dichloromethane- methanol                   50                                                                                 0 #STR62##         3 64 184-185                                                                            dichloromethane isopropyl                   __________________________________________________________________________                                      ether                                        Note 1) NMR(δ ppm in CDCl.sub.3): 1.7-2.1(4H,m), 2.50(3H,s),            2.62(2H,t,J=7Hz), 4.79(1H,dd,J=6, 5&4.5Hz), 5.07(2H,s),                       6.99(2H,d,J=8.5Hz), 7.10(2H,d,J=8.5Hz), 7.45-7.7(3H,m), 7.85-8.0(2H,m),       8.15(1H,dd,J=7&1Hz), 9.21(1H,d,J=8.5Hz).                                      Mc: methyl, 2naph.: 2naphthyl, 1naph.: 1naphthyl                         

EXAMPLE 51

A mixture of 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]cinnamaldehyde(4.00 g), 2,4-oxazolidinedione (2.86 g), piperidine (0.60 g) and ethanol(50 ml) was heated for 2 hours under reflux. The reaction mixture wasconcentrated and the residue was subjected to silica gel columnchromatography. Fractions eluted with ethyl acetate-chloroform (1:4)gave crystals. The crystals were dissolved in tetrahydrofuran (100 ml).To the solution was added palldium-carbon (5%, 1.40 g). The mixture wassubjected to catalytic hydrogenation at room temperature underatmospheric pressure. The catalyst was filtered off, and the filtratewas concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography. From the fractions eluted withchloroform-methanol (100:2),5-[3-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]propyl]-2,4-oxazolidinedione(1.10 g, 21%) was obtained. Recrystallization fromdichloromethane-isopropylether gave colorless prisms. Melting point:126-127° C.

EXAMPLE 52

In substantially the same manner as in Example 51,5-[3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridyl]propyl]-2,4-oxazolidinedionewas obtained as an oily substance. Yield: 22%.

NMR (67 ppm in CDCl₃): 1.7-2.15(4H,m), 2.48(3H,s), 2.61(2H,t,J=7 Hz),4.84(1H,dd,J=6.5&4.5 Hz), 5.27(2H,s), 6.76(1H,d,J=8.5 Hz),7.3-7.5(4H,m), 7.95-8.1(3H,m), 8.84(1H,br s).

EXAMPLE 53

In substantially the same manner as in Example 35,5-[4-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]butyl]-2,4-oxazolidinedionewas obtained. Yield: 22%. Recrystallization fromdichloromethane-methanol gave colorless prisms. Melting point: 163-164°C.

EXAMPLE 54

In substantially the same manner as in Example 35,5-[3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propyl]-2,4-oxazolidinedionewas obtained. Yield: 13%. Recrystallization fromdichloromethane-methanol gave colorless prisms. Melting point: 151-152°C.

EXAMPLE 55

In substantially the same manner as in Example 1,5-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-propenylidene]-2,4-oxazolidinedionewas obtained. Recrystallization from chloroform-methanol gave colorlessneedles. Melting point: 229-230° C.

EXAMPLE 56

In substantially the same manner as in Example 16,5-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-propyl]-2,4-oxazolidinedionewas obtained. Recrystallization from ethyl acetate-hexane gave colorlessneedles. Melting point: 134-135° C.

EXAMPLE 57

In substantially the same manner as in Example 51,5-[3-(4-isopropoxyphenyl)propyl]-2,4-oxazolidinedione was obtained as anoily substance.

NMR (δ ppm in CDCl₃): 1.32(6H,d,J=6 Hz), 1.65-2.15(4H,m), 2.62(2H,t,J=7Hz), 4.4-4.6(1H,m), 4.84(1H,dd,J=7&4.5 Hz), 6.81(2H,d,J=8.5 Hz),7.06(2H,d,J=8.5 Hz), 8.00(1H,broad s).

EXAMPLE 58

In substantially the same manner as in Example 51,5-[5-(4-isopropoxyphenyl)pentyl]-2,4-oxazolidinedione was obtained as anoily substance.

NMR (δ ppm in CDCl₃): 1.32(6H,d,J=6 Hz), 1.3-2.1(8H,m), 2.54(2H,t,J=7.5Hz), 4.4-4.6(1H,m), 4.84(1H,dd,J=7.5&4.5 Hz), 6.80(2H,d,J=8.5 Hz),7.05(2H,d,J=8.5 Hz), 7.98(1H,broad s).

EXAMPLE 59

In substantially the same manner as in Example 35,5-[4-(4-isopropoxyphenyl)butyl]-2,4-oxazolidinedione was obtained byreacting 2-[3-(4-isopropoxyphenyl)-propyl]-1,3-dioxolane with2,4-oxazolidinedione, followed by allowing the reaction product tocatalytic hydrogenation. Recrystallization fromdichloromethane-isopropylether gave colorless prisms. Melting point:81-82° C.

EXAMPLE 60

In substantially the same manner as in Example 51,5-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-butyl]-2,4-oxazolidinedionewas obtained as pale yellow amorphous powder.

NMR(δ ppm in CDCl₃): 1.25(3H,d,J=6.8 Hz), 1.30-2.00(4H,m), 2.43(3H,s),2.55-2.80(1H,m), 4.67-483(1H,m), 4.97(2H,s), 6.95(2H,d,J=8.8 Hz),7.09(2H,d,J=8.8 Hz), 7.35-7.53(3H,m), 7.92-8.10(2H,m).

EXAMPLE 61

In substantially the same manner as in Example 33,5-[3-[4-[2-(2-benzo[b]thienyl)-5-methyl-4-oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedionewas obtained. The yield was 76%. Recrystallization fromdichloromethane-isopropyl ether gave colorless prisms, m.p. 154-155° C.

EXAMPLE 62

In substantially the same manner as in Example 33,5-[3-[4-[2-(2-benzo[b]furanyl)-5-methyl-4-oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedionewas obtained. The yield was 70%. Recrystallization fromdichloromethane-isopropyl ether gave colorless needles, m.p. 165-166° C.

Formulation Example 1

(Preparation of tablets)

    ______________________________________                                        (1) 5-[3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-                       pyridyl]propyl]-2,4-oxazolidinedione                                                                      10 g                                              (2) lactose                 50 g                                              (3) corn starch             15 g                                              (4) carboxymethylcellulose calcium                                                                        44 g                                              (5) magnesium stearate       1 g                                              1000 tablets                120 g                                             ______________________________________                                    

The whole amounts of above (1), (2) and (3), and 30 g of (4) werekneaded with water, which was subjected to vacuum drying, followed bygranulation. Thus-granulated powder was mixed with 14 g of (4) and 1 gof (5), followed by tableting using a tableting machine to prepare 1000tablets containing 10 mg of (1) per tablet.

Formulation Example 2

Preparation of tablets

    ______________________________________                                        (1) 5-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl]-                                                         30 g                                                 ethoxy]phenyl]ethyl]-2,4-oxazolidinedione                                     (2) lactose              50 g                                                 (3) corn starch          15 g                                                 (4) carboxymethylcellulose calcium                                                                     44 g                                                 (5) magnesium stearate    1 g                                                 1000 tablets             140 g                                                ______________________________________                                    

The whole amounts of above (1), (2) and (3), and 30 g of (4) werekneaded with water, which was subjected to vacuum drying, followed bygranulation. Thus-granulated powder was mixed with 14 g of (4) and 1 gof (5), which was tableted by using a tableting machine to prepare 1000tablets containing 30 mg of (1) per tablet.

Reference Example 1

To a solution of triethyl phosphonoacetate (1.79 g), inN,N-dimethylformamide (40 ml) was added, little by little at 0° C.sodium hydride (60% in oil, 0.32 g). The mixture was stirred for 15minutes at the same temperature. To the reaction mixture was added4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]benzaldehyde (2.44g), and the mixture was stirred for one hour at room temperature. Thereaction mixture was poured into ice-water, which was acidified with 2NHCl, and resulting crystalline precipitate was collected by filtration.Recrystallization from ethyl acetate-hexane gave ethyl(E)-4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamate (2.52g, 85%) as colorless needles, m.p.90-91° C.

Reference Example 2 to Reference Example 6

In substantially the same manner as in Reference Example 1, compoundsshown in [Table 7] were obtained.

                                      TABLE 7                                     __________________________________________________________________________    1 #STR63##                                                                    Reference                                                                     Example                   Yield                                                                            m.p. Recrystallization                           No.  R                 R.sup.2                                                                          (%)                                                                              (° C.)                                                                      solvent                                     __________________________________________________________________________         2 #STR64##        CH.sub.3                                                                         83 84-85                                                                              ethyl ether- hexane                         3                                                                                  3 #STR65##        C.sub.2 H.sub.5                                                                  90 77-78                                                                              ethyl ether- hexane                         4                                                                                  4 #STR66##        C.sub.2 H.sub.5                                                                  88 81-82                                                                              ethyl ether- hexane                         5                                                                                  5 #STR67##        C.sub.2 H.sub.5                                                                  95 69-70                                                                              hexane                                      6                                                                                  6 #STR68##        C.sub.2 H.sub.5                                                                  96 121-122                                                                            ethyl acetate- hexane                       __________________________________________________________________________

Reference Example 7

A toluene solution of diisobutylaluminum hydride (1.5M, 9.3 ml) wasadded dropwise at 0° C. to a suspension of ethyl(E)-4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamate (2.48g) in dichloromethane (50 ml). The mixture was stirred for 2 hours atroom temperature, to which were then added, under ice-cooling, methanol(3 ml) and, then, water (30 ml). The mixture was subjected to filtrationthrough a celite layer. The organic layer was washed with water, dried(MgSO₄) and, then, concentrated. The concentrate was purified by meansof a column chromatography. From the fractions eluted with ethylacetate-hexane (1:1) was obtained(E)-3-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]phenyl]-2-propen-1-ol(1.44 g, 65%). Recrystallization from dichloromethane-isopropyl ethergave colorless prisms, m.p.116-117° C.

Reference Example 8 to Reference Example 13

In substantially the same manner as in Reference Example 7, compoundsshown in [Table 8] were obtained.

                                      TABLE 8                                     __________________________________________________________________________    9 #STR69##                                                                    Reference                                                                     Example                Yield                                                                            m.p. Recrystallization                              No.  R                 (%)                                                                              (° C.)                                                                      solvent                                        __________________________________________________________________________         2 #STR70##        81 Note 1) oily product                                                               --                                             9                                                                                  9 #STR71##        90 127-128                                                                            ethyl acetate                                  10                                                                                 3 #STR72##        68 124-125                                                                            dichloromethane- isopropyl ether               11                                                                                 4 #STR73##        81 113-114                                                                            dichloromethane- isopropyl ether               12                                                                                 5 #STR74##        29 110-111                                                                            ethyl acetate- hexane                          13                                                                                 6 #STR75##        85 139-140                                                                            ethyl acetate                                  __________________________________________________________________________     Note 1) NMR(δ ppm in CDCl.sub.3): 1.24(3H, t, J=7.5Hz), 2.63(2H, q,     J=7.5Hz), 3.23(2H, t, J=7Hz), 4.25-4.4(4H, m), 6.23(1H, dt, J=16&6Hz),        6.55(1H, d, J=16Hz), 6.86(2H, d, J=9Hz), 7.19(1H, d, J=8Hz), 7.30(2H, d,      J=9Hz), 7.46(1H, dd, J=8&2Hz), 8.40(1H, d, J=2Hz).                       

Reference Example 14

Activated manganese dioxide (2.8 g) was added to a solution of(E)-3-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]phenyl]-2-propen-1-ol(1.4 g) in dichloromethane (50 ml). The mixture was stirred for 2 hoursat room temperature, which was subjected to filtration through celite.The filtrate was concentrated to give(E)-4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamaldehyde(1.2 g, 91%). Recrystallization from dichloromethane-isopropyl ethergave colorless needles, m.p.110-111° C.

Reference Example 15 to Reference Example 20

In substantially the same manner as in Reference Example 14, compoundsshown in [Table 9] were obtained.

                                      TABLE 9                                     __________________________________________________________________________    7 #STR76##                                                                    Reference                                                                     Example                Yield                                                                            m.p. Recrystallization                              No.  R                 (%)                                                                              (° C.)                                                                      solvent                                        __________________________________________________________________________    15                                                                                 8 #STR77##        84 50-51                                                                              ethyl ether- hexane                            16                                                                                 9 #STR78##        94 128-129                                                                            ethyl acetate- hexane                          17                                                                                 0 #STR79##        97 120-121                                                                            dichlromethane- isopropyl ether                18                                                                                 1 #STR80##        93 103-104                                                                            dichloromethane- isopropyl ether               19                                                                                 2 #STR81##        93 133-134                                                                            ethyl acetate- ethyl ether                     20                                                                                 3 #STR82##        88 128-129                                                                            ethyl acetate- hexane                          __________________________________________________________________________

Reference Example 21

To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde(3.0 g) and pyruvic acid (3.44 g) in methanol (80 ml) was added dropwisea solution of sodium carbonate (4.14 g) in water (80 ml). The mixturewas stirred for 24 hours at temperatures ranging from 70 to 80° C.,which was poured into water, followed by washing with ethyl acetate. Theaqueous layer was acidified with conc. HCl, then resulting crystallineprepcipitate was collected by filtration. The crystals were added toethanol containing hydrogen chloride (5%, 15 ml), and the mixture washeated for 30 minutes under reflux. The solvent was distilled off underreduced pressure. The residue was dissolved in chloroform. The solutionwas washed with water, dried (MgSO₄) and, then, concentrated. Theconcentrate was purified by means of a silica gel column chromatography.From the fractions eluted with ethyl acetate-chloroform (1:9) wasobtained ethyl (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidenepyruvate (1.0 g, 25%). Recrystallization from dichloromethane-ethanolgave pale yellow needles, m.p.99-100° C.

Reference Example 22

A mixture of ethyl(E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidene pyruvate (0.85g), palladium-carbon (10%, 0.1 g) and dioxane (80 ml) was subjected tocatalytic hydrogenation at room temperature under atmospheric pressure.The catalyst was filtered off. The filtrate was concentrated underreduced pressure. The concentrate was dissolved in ethanol (20 ml). Tothe solution was added, under ice-cooling, sodium borohydride (0.08 g),and the mixture was stirred for one hour at room temperature. Thereaction mixture was poured into water and neutralized with 1N HCl,followed by extraction with ethyl acetate. The ethyl acetate layer waswashed with water, dried (MgSO₄) and, then concentrated. The concentratewas purified by means of a silica gel column chromatography. From thefractions eluted with chloroform-ethyl acetate (9:1) was obtained ethyl2-hydroxy-4-(4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyrate(0.55 g, 64%). Recrystallization from ethyl ether-hexane gave colorlessneedles, m.p.67-68° C.

Reference Example 23

To a stirred solution of 2-chloro-5-nitropyridine (25 g),2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (32.1 g) in THF (250 ml) wasadded portionwise, under ice-cooling, sodium hydride (60% in oil, 6.92g). The reaction mixture was stirred for further 15 hours at roomtemperature, which was poured into water, followed by extraction withethyl acetate. The ethyl acetate was washed with water and dried(MgSO₄), then the solvent was distilled off under reduced pressure. Theresidual crystals were collected by filtration. Recrystallization fromethanol gave 2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-nitropyridine(25.4 g, 49%) as yellowish brown crystals, m.p.110.5-111.5° C.

Elemental Analysis for C₁₇ H₁₅ N₃ O₄ : Calcd.: C, 62.76; H, 4.65; N,12.92 Found: C, 62.80; H, 4.58; N, 12.96

Reference Example 24

A mixture of 2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-nitropyridine(13.4 g), palladium-carbon (5%, 1.5 g) and ethyl acetate (200ml)-methanol (150 ml) was subjected catalytic hydrogenation at roomtemperature under one atmospheric pressure. The catalyst was filteredoff, and the filtrate was concentrated under reduced pressure. Theresidual crystals were collected by filtration to obtain5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (11.4 g,93%). Recrystallization from ethyl acetate-hexane gave brown crystals,m.p.107.0-108.0° C.

Elemental Analysis for C₁₇ H₁₇ N₃ O₂ : Calcd.: C, 69.14; H, 5.80; N,14.23 Found: C, 69.01; H, 5.94; N, 13.99

Reference Example 25

To a mixture of5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (10.0 g),conc. HCl (8.47 ml) and acetone (100 ml) was added dropwise a solutionof sodium nitrite (NaNO₂) (2.46 g) in water (10 ml) at temperaturesbelow 10° C. The mixture was stirred for 30 minutes at 10° C., to whichwas dropwise added a solution of potassium iodide (KI) (2.46 g) in water(10 ml) at 10° C. The reaction mixture was stirred for further one hourat temperatures raging from 30 to 35° C. and for another one hour attemperatures ranging from 35 to 40° C., followed by concentration underreduced pressure. The concentrate was poured into water, which wassubjected to extraction with ethyl acetate. The ethyl acetate layer waswashed with water and dried (MgSO₄), then the solvent was distilled offunder reduced pressure. The residual oily product was subjected to asilica gel chromatography. From the fractions eluted with ethylacetate-hexane (1:3, v/v) was obtained5-iodo-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (7.22 g, 52%).Recrystallization from ethyl acetate-hexane gave colorless crystals,m.p.105-106° C.

Elemental Analysis for C₁₇ H₁₅ N₂ O₂ I: Calcd.: C., 50.26; H, 3.72; N,6.90 Found: C, 50.22; H, 3.89; N, 6.78

Reference Example 26

To a solution of5-iodo-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (2.5 g) intetrahydrofuran (40 ml) was added dropwise, at -65° C. under nitrogenstreams, a hexane solution of n-butyllithium (1.6M, 4.61 ml). Themixture was stirred for 15 minutes at the same temperature, to which wasadded dropwise N,N-dimethylformamide (0.71 ml). The cooling bath wasremoved, then the reaction mixture was stirred for further 30 minutes,to which was added a saturated aqueous solution of ammonium chloride (6ml). The reaction mixture was poured into water, followed by extractionwith ethyl acetate. The ethyl acetate was washed with water and dried(MgSO₄), then the solvent was distilled off under reduced pressure toleave 5-formyl-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (1.5g, 79%). Recrystallization from ethyl acetate-hexane gave colorlesscrystals, m.p.99-100° C.

Elemental Analysis for C₁₈ H₁₆ N₂ O₃ : Calcd.: C, 70.12; H, 5.23; N,9.09 Found: C, 69.94; H, 5.38; N, 8.94

Reference Example 27

In substantially the same manner as in Reference Example 1, was obtainedmethyl 3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl]ethoxy]-5-pyridyl]acrylate.Recrystallization from ethyl acetate gave colorless crystals,m.p.138-139° C.

Reference Example 28

In substantially the same manner as in Reference Example 7,(E)-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy]-5-pyridyl]-2-propen-1-olwas obtained. Recrystallization from ethyl acetate-isopropyl ether gavecolorless crystals, m.p.115-116° C.

Reference Example 29

In substantially the same manner as in Reference Example 14,(E)-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy]-5-pyridyl]acrolein.Recrystallization from ethyl acetate-hexane gave colorless crystals,m.p.138-139° C.

Reference Example 30

A mixture of methyl2-bromo-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate(15.0 g), 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) (6.2 g) and toluene(200 ml) was stirred for 2 hours at 70° C. The reaction mixture waspoured into ethyl acetate (200 ml), which was washed with 2N HCl and asaturated aqueous saline solution, followed by drying (MgSO₄). Thesolvent was distilled off under reduced pressure to leave methyl4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamate (10.8 g, 88%).Recrystallization from ethyl acetate-hexane colorless needles,m.p.114-115° C.

Reference Example 31

Sodium hydride (60% in oil, 0.78 g) was added in limited amounts, atroom temperature, to a solution of[2-(1,3-dioxan-2-yl)ethyl]triphenylphosphonium bromide (8.9 g) inN,N-dimethylformamide (100 ml). The mixture was stirred for 30 minutesat the same temperature range, to which was added4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (5.0 g). Themixture was stirred for 15 minutes at room temperature, then for 5 hoursat 70° C. The reaction mixture was poured into ice-water, which wasacidified with 2N HCl, followed by extraction with ethyl acetate. Theethyl acetate layer was washed with water and dried (MgSO₄). The residuewas purified by means of a silica gel column chromatography. From thefractions eluted with hexane-ethyl acetate (3:1),(Z)-2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2-propenyl]-1,3-dioxane(5.1 g, 77%) was obtained as an oily product.

NMR (δ ppm in CDCl ₃): 1.25-1.4(1H,m), 1.95-2.25(1H,m), 2.37(3H,s),2.66(1H,ddd,J=7&5&2 Hz), 2.98(2H,t,J=6.5 Hz), 3.7-3.85(2H,m),4.0-4.3(4H,m), 4.63(1H,t,J=5 Hz), 5.64(1H,dt,J=11.5&7 Hz), 6.48(1H,brd,J==11.5 Hz), 6.85(2H,d,J=9 Hz), 7.22(2H,d,J=9 Hz), 7.35-7.5(3H,m),7.9-8.0(2H,m).

Reference Example 32

A mixture of(Z)-2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2-propenyl]-1,3-dioxane(5.0 g), palladium-carbon (5%, 0.1 g) and ethanol (100 ml) was subjectedto catalytic hydrogenation at room temperature under one atmosphericpressure. The catalyst was filtered off, and the filtrate wasconcentrated under reduced pressure. The concentrate was purified bymeans of a silica gel column chromatography. From the fractions elutedwith hexane-ethyl acetate (1:1),2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-1,3-dioxane(4.8 g, 96%) was obtained. NMR (δ ppm in CDCl₃): 1.25-1.4(1H,m),1.5-1.8(4H,m), 1.9-2.2(1H,m), 2.37(3H,s), 2.54(2H,t,J=7 Hz),2.96(2H,t,J=6.5 Hz), 3.65-3.85(2H,m), 4.0-4.15(2H,m), 4.21(2H,t,J=6.5Hz), 4.50(1H,t,J=5 Hz), 6.80(2H,d,J=9 Hz), 7.06(2H,d,J=9 Hz),7.35-7.5(3H,m), 7.9-8.0(2H,m).

Reference Example 33 to Reference Example 36

In substantially the same manner as in Reference Example 1, compoundsshown in [Table 10] were obtained.

                                      TABLE 10                                    __________________________________________________________________________    4 #STR83##                                                                    Reference                                                                     Example                    Yield                                                                            m.p. Recrystallization                          No.  R                     (%)                                                                              (° C.)                                                                      solvent                                    __________________________________________________________________________    33                                                                                 5 #STR84##            88 126-127                                                                            diethyl ether- isopropyl ether             34                                                                                 6 #STR85##            86 111-112                                                                            dichloromethane- isopropyl ether           35                                                                                 7 #STR86##            89 oily product.sup.1)                             36                                                                                 8 #STR87##            96 145-146                                                                            ethyl acetate- hexane                      __________________________________________________________________________     Note .sup.1) NMR(δ ppm in CDCl.sub.3):1.30(3H, t, J=7.5Hz), 1.33(3H     t, J=7Hz), 2.25(3H, s), 2.70(2H, q, J=7.5Hz), 2.88(1H, t, J=7Hz), 4.20(2H     t, J=7Hz), 4.25(2H, q, J=7.5Hz), 6.29(1H, d, J=16Hz), 6.88(2H, d, J=9Hz),     7.45(2H, d, J=9Hz), 7.63(1H, d, J=16Hz).                                 

Reference Example 37

In substantially the same manner as in Reference Example 1, by reactionof 5-formyl-2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran withtriethyl phosphonoacetate, was obtained ethyl(E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]acrylate.Yield was 74%. Recrystallization from ether-hexane gave colorlessprisms, m.p. 150-151° C.

Reference Example 38

In substantially the same manner as in Reference Example 1, by reactionof (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamaldehyde withtriethyl phosphonoacetate, was obtained ethyl(E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadienoate.The yield was 56%. Recrystallization from ether-hexane gave colorlessneedles, m.p. 102-103° C.

Reference Example 39

A mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (2.9g), sodium pyruvate (3.3 g), sodium carbonate (3.2 g), water (80 ml) andmethanol (80 ml) was stirred for 6 hours under reflux. The reactionmixture was concentrated under reflux to about 1/3 of the initialvolume. The concentrate was subjected to extraction with ethyl acetate.The aqueous layer was acidified with conc. HCl. Resulting crystallineprecipitate was collected by filtration to obtain(E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvic acid (1.6g, 44%). Recrystallization from chloroform-methanol gave colorlessneedles, m.p.197-198° C.

Reference Example 40

To a mixture of(E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvic acid (1.3g) and ethanol (50 ml) was added conc. sulfuric acid (0.1 ml). Themixture was heated for 8 hours under reflux, then the reaction mixturewas poured into water, which was subjected to extraction with ethylacetate. The ethyl acetate layer was washed with water and dried(MgSO₄), followed by distilling off the solvent. The residue wassubjected to a silica gel column chromatography. From the fractionseluted with ethyl acetate-hexane (1:3, v/v), ethyl(E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvate (1,2 g,86%) was obtained. Recrystallization from ethyl acetate-hexane gave paleyellow prisms. Melting point: 110-111° C.

Reference Example 41

In substantially the same manner as in Reference Example 22, from ethyl(E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvate, wasobtained ethyl2-hydroxy-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]butyrate. Theyield was 89%.

NMR (δ ppm CDCl₃): 1.28(3H,t,J=7 Hz), 1.8-2.2(2H,m), 2.43(3H,s),2.71(2H,t,J=7 Hz), 2.84(1H,d,J=5.2 Hz), 4.1-4.3(1H,m), 4.21(2H,q,J=7Hz), 4.97(2H,s), 6.94(2H,d,J=9 Hz), 7.13(2H,d,J=9 Hz), 7.4-7.5(3H,m),7.95-8.1(2H,m).

Reference Example 42 to Reference Example 45

In substantially the same manner as in Reference Example 7, compoundsshown in [Table 11] were obtained.

                                      TABLE 11                                    __________________________________________________________________________    9 #STR88##                                                                    Reference                                                                     Example                    Yield                                                                            m.p. Recrystallization                          No.  R                     (%)                                                                              (° C.)                                                                      solvent                                    __________________________________________________________________________    42                                                                                 0 #STR89##            84 123-124                                                                            dichloromethane- isopropyl ether           43                                                                                 1 #STR90##            81 134-135                                                                            dichloromethane- isopropyl ether           44                                                                                 2 #STR91##            34 oily product.sup.1)                             45                                                                                 3 #STR92##            97 133-134                                                                            ethyl acetate- hexane                      __________________________________________________________________________     Note .sup.1) NMR(δ ppm in CDCl.sub.3):1.30(3H, t, J=7.5Hz),             1.3-1.5(1H, m), 2.45(3H, s), 2.70(2H, q, J=7.5Hz), 2.87(2H, t, J=7Hz),        4.17(2H, t, J=7Hz), 4.25-4.35(2H, m), 6.23(1H, dt, J=16&6Hz), 6.55(1H, d,     J=16Hz), 6.83(2H, d, J=9Hz), 7.30(2H, d, J=9Hz).                         

Reference Example 46

In substantially the same manner as in Reference Example 7, ethyl(E)-3-[2-(5-methyl-2-phenyl-4-oxazolyl methyl)benzofuran-5-yl]acrylatewas subjected to reduction to give(E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]-2-propen-1-ol.The yield was 57%. Recrystallization from dichloromethane-hexane gavecolorless needles, m.p. 156-157° C.

Reference Example 47

In substantially the same manner as in Reference Example 7, ethyl(E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadienoatewas subjected to reduction to give(E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadien-1-ol.The yield was 63%. Recrystallization from dichloromethane-hexane gavecolorless scales, m.p.132-133° C.

Reference Example 48 to Reference Example 51

In substantially the same manner as in Reference Example 14, compoundsshown in [Table 12] were obtained.

                                      TABLE 12                                    __________________________________________________________________________    4 #STR93##                                                                    Reference                                                                     Example                    Yield                                                                            m.p. Recrystallization                          No.  R                     (%)                                                                              (° C.)                                                                      solvent                                    __________________________________________________________________________    48                                                                                 5 #STR94##            84 115-116                                                                            dichloromethane- isopropyl ether           49                                                                                 6 #STR95##            91 155-156                                                                            dichloromethane- isopropyl ether           50                                                                                 7 #STR96##            95 oily product.sup.1)                             51                                                                                 8 #STR97##            70 114-115                                                                            ethyl acetate- hexane                      __________________________________________________________________________     Note .sup.1) NMR(δ ppm in CDCl.sub.3):1.30(3H, t, J=7.5Hz), 2.25(3H     s), 2.71(2H, q, J=7.5Hz), 2.90(2H, t, J=6.5Hz), 4.23(2H, t, J=6.5Hz),         6.60(1H, dd, J=16&7.5Hz), 6.93(2H, d, J=9Hz), 7.41(1H, d, J=16Hz),            7.50(2H, d, J=9Hz), 9.65(1H, d, J=7.5Hz).                                

Reference Example 52

In substantially the same manner as in Reference Example 14, from(E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]-2-propen-1-ol,was obtained(E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]acrolein.The yield was 93%. Recrystallization from dichloromethane-hexane gavecolorless needles, m.p.136-137° C.

Reference Example 53

In substantially the same manner as in Reference Example 14, from(E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadien-1-ol,was obtained(E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]2,4-pentadien-1-al.The yield was 82%. Recrystallization from dichloromethane-hexane gaveyellow prisms, m.p.133-134° C.

Reference Example 54

A mixture of 4-bromoacetyl-5-methyl-2-phenyloxazole (2.60 g),4-[2-(1,3-dioxolan-2-yl)ethyl]phenol (1.82 g), potassium carbonate (1.28g) and 2-butanone (60 ml) was stirred for 20 hours at temperaturesranging from 70 to 80° C. The reaction mixture was poured into water.Resulting crystalline precipitate was collected by filtration, which waspurified by means of a silica gel column chromatography. From thefractions eluted with chloroform-methanol (100:1, v/v),4-[4-[2-(1,3-dioxolan-2-yl)ethyl]phenoxyacetyl]-5-methyl-2-phenyloxazole(2.08 g, 57%) was obtained. Recrystallization fromdichloromethane-isopropyl ether gave colorless prisms, m.p.119-120° C.

Reference Example 55

In substantially the same manner as in Reference Example 1, ethyl4-[2-[N-methyl-N-(2-pyridyl)amino]-ethoxy]cinnamate was obtained. Yield:97%. Recrystallization from dichloromethane-isopropyl ether gavecolorless prisms. Melting point 80-81° C.

Reference Example 56

In substantially the same manner as in Reference Example 1, ethyl(E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridyl]acrylate wasobtained. Yield: 86%. Recrystallization from dichloromethane-isopropylether gave colorless prisms. Melting point: 109-110° C.

Reference Example 57

In substantially the same manner as in Reference Example 7,(E)-3-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]-2-propen-1-olwas obtained as an oily substance. Yield: 87%.

NMR (δ ppm in CDCl₃): 3.14(3H,s), 3.98(2H,t,J=5.5 Hz), 4.19(2H,t,J=5.5Hz), 4.29(2H,br d, J=5.5 Hz), 6.22(1H,dt,J=16&6 Hz), 6.45-6.6(3H,.m),6.85(2H,d,J=9 Hz), 7.30(2H,d,J=9 Hz), 7.45(1H,ddd,J=8.5&7&2 Hz),8.1-8.2(1H,m).

Reference Example 58

In substantially the same manner as in Reference Example 7,(E)-3-[2-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-5-pyridyl]-2-propen-1-olwas obtained. Yield: 57%. Recrystallization fromdichloromethane-isopropyl ether gave colorless prisms. Melting point:116-117° C.

Reference Example 59

In substantially the same manner as in Reference Example 14,4-[2-[N-methyl-N-(2-pyridyl)amino]-ethoxy]cinnamaldehyde was obtained asan oily substance. Yield: 100%.

NMR (δ ppm in CDCl₃): 3.15(3H,s), 4.01(2H,t,J=5.5 Hz), 4.25(2H,t,J=5.5Hz), 6.5-6.7(3H,m), 6.95(2H,d,J=9 Hz), 7.41(1H,d,J=16 Hz),7.4-7.55(3H,m), 8.16(1H,ddd,J=5&2&1 Hz), 9.65(1H,d,J=8 Hz).

Reference Example 60

In substantially the same manner as in Reference Example 14,(E)-3-[2-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-5-pyridyl]acrolein wasobtained. Yield: 92%. Recrystallization from dichloromethane-isopropylether gave colorless prisms. Melting point: 147-148° C.

Reference Example 61

A solution of n-butyllithium in hexane (1.62M, 25.9 ml) was addeddropwise to a suspension of[2-(1,3-dioxolan-2-yl)ethyl]triphenylphosphonium bromide (18.6 g) intetrahydrofuran (180 ml) at -20° C. The mixture was stirred for 2 hours.To the reaction mixture was added4-[2-(2-naphthyl)-5-methyl-4-oxazolylmethoxy]benzaldehyde (12.0 g). Themixture was stirred at 50-55° C. for 4 hours. The reaction mixture waspoured into ice-water, followed by subjecting extraction with ethylacetate.

The ethyl acetate layer was washed with 0.1N-hydrochloric acid and waterin the order mentioned and dried over magnesium sulfate. The solvent wasdistilled off. The residue was subjected to silica gel columnchromatography. From the fraction eluted with chloroform-methanol(100:5), crystals (14.8 g) were obtained. The crystals were dissolved intetrahydrofuran (250 ml). To the solution was added palladium-carbon(5%, 3.0 g). The mixture was subjected to catalytic hydrogenation atroom temperature under atmospheric pressure. The catalyst was filteredoff. The filtrate was concentrated under reflux, whereby4-[4-[3-(1,3-dioxolan-2-yl)propyl]phenoxymethyl]-5-methyl-2-(2-naphthyl)oxazole(12.1 g, 81%) was obtained. Recrystallization fromdichloromethane-isopropyl ether gave colorless prisms. Melting point:141-142° C.

Reference Example 62

In substantially the same manner as in Reference Example 1, ethyl(E)-4-hydroxy-3-nitrocinnamate was obtained by reacting4-hydroxy-3-nitrobenzaldehyde with triethyl phosphonoacetate.Recrystallization from dichloromethane-isopropyl ether gave pale yellowneedles. Melting point: 114-115° C.

Reference Example 63

In substantially the same manner as in Reference Example 24, ethyl3-(3-amino-4-hydroxyphenyl)propionate was obtained as an oily substanceby subjecting ethyl (E)-4-hydroxy-3-nitrocinnamate to catalyticreduction.

NMR (δ ppm in CDCl₃): 1.24(3H,t,J=7 Hz), 2.5-2.9(4H,m), 4.12(2H,q,J=7Hz), 6.49(1H,dd,J=8&2 Hz), 6.60(1H,d,J=2 Hz), 6.64(1H,d,J=8 Hz).

Reference Example 64

A mixture of phosphorus pentoxide (P₂ O₅) (12.9 g), hexamethyldisiloxane(29.5 g) and 1,2-dichlorobenzene was heated for 10 minutes under reflux.To the mixture were added ethyl 3-(3-amino-4-hydroxyphenyl)propionate(4.75 g) and 2-naphthylacetic acid (4.23 g). The mixture was heated for3 hours under reflux. The reaction mixture was poured into water andallowed to extraction with ethyl acetate. The ethyl acetatae layer waswashed with water and dried over magnesium sulfate. The solvent wasdistilled off, and the residue was subjected to silica gel columnchromatography. From the fractions eluted with ethyl acetate-hexane(1:4, v/v), ethyl 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionate(5.95 g, 73%) was obtained. Recrystallization from ether-isopropyl ethergave colorless needles. Melting point: 81-82° C.

Reference Example 65

To a solution of ethyl3-[2-(2-naphthylmethyl)-benzoxazol-5-yl]propionate (5.8 g) in ether (100ml)-tetrahydrofuran (100 ml) was added lithium aluminum hydride (0.73g), and the mixture was stirred at room temperature for one hour. To thereaction mixture was added water (4 ml). Insolubles were filtered off.The filtrate was concentrated under reduced pressure, and the residuewas subjected to silica gel column chromatography. From the fractioneluted with ethyl acetate-hexane (1:1, v/v),3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propanol (2.1 g, 41%) wasobtained. Recrystallization from dichloromethane-isopropylether gavecolorless prisms. Melting point: 102-103° C.

Reference Example 66

Oxalyl chloride[(COCl)₂ ] (0.88 g) was added dropwise to a solution ofdimethyl sulfoxide (DMSO) (1.0 g) in dichloromethane (30 ml) at -30° C.To the mixture was added3-[2-(2-naphthylmethyl)benzoxazol-5-yl]-propanol (2.0 g). The mixturewas stirred for 30 minutes at the same temperature. To the mixture wasadded triethyl amine (3.19 g). The mixture was stirred for 30 minutes,warmed to 0° C. and poured into 2N HCl. The organic layer was separated,washed with water and dried over magnesium sulfate (MgSO₄). The solventwas distilled off, and the residue was subjected to silica gel columnchromatography. From the fractions eluted with ethyl acetate-hexane(1:2, v/v), 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionaldehyde (1.54g, 77%) was obtained. Recrystallization from ether-isopropyl ether gavecolorless needles. Melting point: 81-82° C.

Reference Example 67

A mixture of 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionaldehyde (2.9g), ethylene glycol (0.685 g), P-toluenesulfonic acid monohydrate (0.175g) and benzene (50 ml) was stirred for 3 hours under reflux. Thereaction mixture was successively washed with aqueous solution of sodiumhydrogencarbonate and water, and dried over magnesium sulfate (MgSO₄).The solvent was distilled off, whereby5-[2-(1,3-dioxolan-2-yl)ethyl]-2-(2-naphthylmethyl)benzoxazole (2.95 g,89%) was obtained. Recrystallization from dichloromethane-isopropylether gave colorless prisms. Melting point: 85-86° C.

Reference Example 68

A mixture of 2-chloromethyl-5-methyl-2-phenyloxazole (20.8 g),3-hydroxybenzaldehyde (12.2 g), potassium carbonate (27.6 g) andN,N-dimethylformamide (DMF) (200 ml) was heated at 90° C. for 2 hours.The reaction mixture was poured into water, and subjected to extractionwith ethyl acetate. The ethyl acetate layer was washed with water anddried over magnesium sulfate (MgSO₄). The solvent was distilled off,whereby 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (26.5 g,90%) was obtained. Recrystallization from ethanol gave colorless prisms.Melting point: 67-68° C.

Reference Example 69

In substantially the same manner as in Reference Example 1, ethyl(E)-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate was obtained.Recrystallization from ethanol gave colorless prisms. Melting point:91-92° C.

Reference Example 70

To a solution of ethyl(E)-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate (14.0 g) indichloromethane (200 ml) was added a solution of diisobutylaluminiumhydride in toluene (1.5M, 51 ml) dropwise under ice cooling. Thereaction mixture was stirred for 30 minutes at the same temperature, andto the mixture was added dropwise 2N-HCl (150 ml). The organic layer wasseparated, washed with water and dried over magnesium sulfate (MgSO₄).The solvent was distilled off, whereby(E)-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-propen-1-ol (11.5g, 92%) was obtained. Recrystallization from ethyl acetate gavecolorless prisms. Melting point: 120-121° C.

Reference Example 71

In substantially the same manner as in Reference Example 14,(E)-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamaldehyde was obtained.Recrystallization from ethanol acetate-hexane gave colorless rods.Melting point: 103-104° C.

Reference Example 72

In substantially the same manner as in Reference Example 23,2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-nitropyridine was obtained.Recrystallization from dichloromethane-isopropyl ether gave pale yellowprisms. Melting point: 142-143° C.

Reference Example 73

In substantially the same manner as in Reference Example 24,5-amino-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine was obtained.Recrystallization from methanol-isopropyl ether gave colorless prisms.Melting point: 106-107° C.

Reference Example 74

In substantially the same manner as in Reference Example 25,5-iodo-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine was obtained.Recrystallization from ethyl-acetate gave colorless prisms. Meltingpoint: 129-130° C.

Reference Example 75

In substantially the same manner as in Reference Example 26,5-formyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine was obtained.Recrystallization from ethyl acetate-hexane gave colorless prisms.Melting point: 116-117° C.

Reference Example 76

To a mixture of 4-benzyloxybenzaldehyde (4.5 g),(1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide andN,N-dimethylformamide (DMF) (50 ml) was added sodium hydride (60% inoil, 0.935 g). The mixture was stirred for 3 hours at 60° C. Thereaction mixture was poured into ice-water and neutralized with 2N-HCl.The mixture was subjected to extraction with ethyl acetate. The ethylacetate layer was washed with water and dried over magnesium sulfate(MgSO₄). The solvent was distilled off, and the residue was subjected tosilica gel column chromatography. From the fractions eluted withchloroform, 2-vinyl-1,3-dioxolane derivative (5.7 g) was obtained as anoily substance. The oily substance was dissolved in ethanol (150 ml). Tothe solution was added palladium-carbon (5%, 2.0 g), and the mixture wassubjected to catalytic hydrogenation at room temperature underatmospheric pressure. The catalyst was filtered off, and the filtratewas concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography. From the fractions eluted withchloroform-ethyl acetate (50:1, v/v),2-[2-(4-hydroxyphenyl)ethyl]-1,3-dioxolane was obtained as an oilysubstance.

NMR (δ ppm in CDCl₃): 1.85-2.0(2H,m), 2.6-2.75(2H,m), 3.8-4.15(4H,m),4.82(1H,broad s), 4.88(1H,t,J=4.5 Hz), 6.75(2H,d,J=8.5 Hz),7.07(2H,d,J=8.5 Hz).

Reference Example 77

In substantially the same manner as in Reference Example 1, crude ethyl(E)-4-isopropoxycinnamate was obtained. The crude substance wassubjected to silica gel column chromatography, and eluted withether-hexane (1:5, v/v).

NMR (δ ppm in CDCl₃): 1.33(3H,t,J=7 Hz), 1.35(6H,d,J=6 Hz),4.25(2H,q,J=7 Hz), 4.5-4.7(1H,m), 6.30(1H,d,J=16 Hz), 6.87(2H,d,J=9 Hz),7.46(2H,d,J=9 Hz), 7.63(1H,d,J=16 Hz).

Reference Example 78

In substantially the same manner as in Reference Example 7, crude(E)-3-(4-isopropoxyphenyl)-2-propen-1-ol was obtained. The crudesubstance was subjected to silica gel column chromatography, and elutedwith ethyl acetate-hexane (1:4, v/v).

NMR (δ ppm in CDCl₃): 1.33(6H,d,J=6 Hz), 1.38(1H,t,J=6 Hz),4.30(2H,dt,J=6&1.5 Hz), 4.45-4.65(1H,m), 6.23(1H,dt,J=16&6 Hz),6.56(1H,d,J=16 Hz), 6.84(2H,d,J=8.5 Hz), 7.31(2H,d,J=8.5 Hz).

Reference Example 79

In substantially the same manner as in Reference Example 14,(E)-4-isopropoxycinnamaldehyde was obtained as an oily substance.

NMR (δ ppm in CDCl₃): 1.37(6H,d,J=6 Hz), 4.5-4.7(1H,m),6.61(1H,dd,J=16&8 Hz), 6.92(2H,d,J=9 Hz), 7.42(1H,d,J=16 Hz),7.51(2H,d,J=9 Hz).

Reference Example 80

To a solution of 5-[3-(4-isopropoxyphenyl)propyl]-2,4-oxazolidinedione(1.5 g) in dichloromethane (70 ml) was added dropwise titaniumtetrachloride (TiCl₄) (4.1 g) at 0° C. The mixture was stirred for onehour at the same temperature. The reaction mixture was poured intoice-water, and subjected to extraction with ethyl acetate. The ethylacetate layer was washed with water and dried over magnesium sulfate(MgSO₄). The solvent was distilled off, and the residue was subjected tosilica gel column chromatography. From the fractions eluted with ethylacetate-hexane (1:4, v/v),5-[3-(4-hydroxyphenyl)propyl]-2,4-oxazolidinedione (0.755 g, 59%) wasobtained. Recrystallization from acetone-hexane gave colorless prisms.Melting point: 132-133° C.

Reference Example 81

To a mixture of 4-isopropoxybenzaldehyde (15.0 g), triethyl4-phosphonocrotonate (27.3 g) and N,N-dimethylformamide (DMF) (100 ml)was added oily sodium hydride (60%, 4.38 g), and the mixture was stirredfor 16 hours at room temperature. The reaction mixture was poured intoice-water, and neutralized with 2N-HCl. The mixture was subjected toextraction with ethyl acetate. The ethyl acetate layer was washed withwater and dried over magnesium sulfate (MgSO₄). The solvent wasdistilled off and the residue was subjected to column chromatography.From the fractions eluted with ether-hexane, ethyl(E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienoate (13.7 g, 58%) wasobtained. Recrystallization from ether-hexane gave colorless prisms.Melting point 64-65° C.

Reference Example 82

In substantially the same manner as in Reference Example 7, ethyl(E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienate was reduced withdiisobutylaluminium hydride to give(E,E)-5-(4-isopropoxyphenyl)-2,4-pentadien-1-ol. Recrystallization fromisopropyl ether gave colorless needles. Melting point 91-92° C.

Reference Example 83

In substantially the same manner as in Reference Example 14,(E,E)-5-(4-isopropoxyphenyl)-2,4-pentadien-1-ol was oxidized withmanganese dioxide to give(E,E)-5-(4-isopropoxyphenyl)-2,4-pentadien-1-al as an oily substance.

NMR (δ ppm in CDCl₃): 1.36(6H,d,J=6 Hz), 4.5-4.7(1H,m),6.22(1H,dd,J=15&8 Hz), 6.8-7.05(4H,m), 7.26(1H,dd,J=J=15&10 Hz),7.44(2H,d,J=9 Hz), 9.59(1H,d,J=8 Hz).

Reference Example 84

In substantially the same manner as in Reference Example 80,5-[5-(4-hydroxyphenyl)pentyl]-2,4-oxazolidinedione was obtained.Recrystallization from ether-isopropyl ether gave colorless prisms.Melting point: 96-97° C.

Reference Example 85

To an ice-cooled solution of[2-(1,3-dioxolan-2-yl)ethyl]triphenylphosphonium bromide (51,0 g) inN,N-dimethylformamide (DMF) (200 ml) was added portionwise sodiumhydride (60% in oil, 4.6 g), and the mixture was stirred for 15 minutes.To the mixture was added 4-isopropoxybenzaldehyde (18.0 g), and themixture was stirred for 5 hours at 80-85° C. The reaction mixture waspoured into ice water, and neutralized with 2N-HCl. The mixture wassubjected to extraction with ether. The ether layer was washed withwater and dried over magnesium sulfate. The solvent was distilled offand the residue was subjected to silica gel column chromatography. Fromthe fractions eluted with ethyl acetate-hexane (1:4, v/v), 1,3-dioxolanederivative (14.5 g) was obtained as an oily substance.

The oily substance was dissolved in ethanol (250 ml). By usingpalladium-carbon (5%, 5.0 g) as catalyst, the solution was subjected tocatalytic reduction at room temperature and atmospheric pressure. Thecatalyst was filtered off and the filtrate was concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography. From the fractions eluted with ethyl acetate-hexane(1:5, v/v), 2-[3-(4-isopropoxyphenyl)propyl]-1,3-dioxolane (6.7 g, 24%)was obtained as an oily substance.

NMR (δ ppm in CDCl₃): 1.32(6H,d,J=6 Hz), 1.6-1.8(4H,m), 2.5-2.65(2H,m),3.8-4.0(4H,m), 4.4-4.6(1H,m), 4.8-4.9(1H,m), 6.8(2H,d,J=8.5 Hz),7.07(2H,d,J=8.5 Hz).

Reference Example 86

In substantially the same manner as in Reference Example 80,5-[4-(4-hydroxyphenyl)butyl]-2,4-oxazolidinedione was obtained.Recrystallization from dichloromethane-methanol gave colorless prisms.Melting point: 151-152° C.

Reference Example 87

In substantially the same manner as in Reference Example 68,4-(5-methyl-2-phenyl-4-oxazolylmethoxy) acetophenone was obtained byreaction of 4-chloromethyl-5-methyl-2-phenyloxazole withp-hydroxyacetophenone. Recrystallization of ethyl acetate-hexane gavecolorless crystals. Melting point: 126-127° C.

Reference Example 88

In substantially the same manner as in Reference Example 1, methyl(E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-butenoate wasobtained by reaction of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)acetophenone with trimethyl phophonoacetate. Recrystallization of ethylacetate-ether gave colorless crystals. Melting point: 125-126° C.

Reference Example 89

In substantially the same manner as in Reference Example 7, methyl(E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-buten-1-ol wasobtained by reduction of methyl(E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl)-2-butenoate withdiisobutylaluminum hydride. Recryatallization of ethyl acetate-ethergave colorless crystals. Melting point: 126-127° C.

Reference Example 90

In substantially the same manner as in Reference Example 14, methyl(E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-buten-1-al wasobtained by oxidation of(E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-buten-1-ol withmanganese dioxide. Recrystallization of ethyl acetate-ether gavecolorless crystals. Melting point: 94-95° C.

We claim:
 1. A 2,4-oxazolidinedione compound of the formula ##STR98##wherein R is oxazolyl, thiazolyl or triazolyl which groups areunsubstituted or are substituted by 1 to 3 substituents selected fromthe group consisting of(1) C₁ -C₃ alkyl, (2) phenyl, (3) naphthyl, (4)furyl, and (5) thienyl; Y is --CO--, CH(OH)-- or NR³ -- wherein R³ is analkyl group which may be substituted; m is 0 or 1; n is 0, 1 or 2; X isN, A is bivalent straight or branched hydrocarbon chain residue having 1to 7 carbon atoms; R¹ and R² each are hydrogen or an alkyl group; L andM each are hydrogen, or L and M are combined with each other to form abond, or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1, which is of the formula ##STR99## or apharmaceutically acceptable salt thereof.
 3. A compound orpharmaceutically acceptable salt thereof as claimed in claim 2, whereinn is 0 or 1; A is a saturated bivalent straight or branched hydrocarbonchain residue having 1 to 4 carbon atoms; and L and M each are hydrogen.4. A compound or pharmaceutically acceptable salt thereof as claimed inclaim 3, wherein A is --CH₂ CH₂ --.
 5. A compound or pharmaceuticallyacceptable salt thereof as claimed in claim 3, wherein R is an oxazolylgroup which is unsubstituted or is substituted by 1 to 3 substituentsselected from the group consisting of (1) C₁ -C₃ alkyl, (2) phenyl, (3)naphthyl, (4) furyl and (5) thienyl.
 6. A compound or pharmaceuticallyacceptable salt thereof as claimed in claim 3, wherein R is an oxazolylgroup which is unsubstituted or is substituted by phenyl, naphthyl,furyl, thienyl or (C₁ -C₃)alkyl.
 7. A compound or pharmaceuticallyacceptable salt thereof as claimed in claim 2, wherein Y is --CO--; n is0; A is a saturated bivalent straight hydrocarbon chain residue having 1to 4 carbon atoms; and L and M each are hydrogen.
 8. A compound orpharmaceutically acceptable salt thereof as claimed in claim 7, whereinR¹ and R² each are hydrogen.
 9. A compound or pharmaceuticallyacceptable salt thereof as claimed in claim 7, wherein A is --CH₂ -- or--CH₂ CH₂ --.
 10. A compound according to claim 1 of the formula:##STR100## or a pharmaceutically acceptable salt thereof.
 11. A compoundaccording to claim 1 whereinm is 0, n is 0, R¹ and R² are each hydrogenor alkyl of 1 to 4 carbon atoms, and A is bivalent straight or branchedhydrocarbon having 1 to 4 carbon atoms,or a pharmaceutically acceptablesalt thereof.
 12. A compound as claimed in claim 1, wherein the compoundis5-[3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy-5-pyridyl]-2-propenylidene]-2,4-oxazolidinedioneor a pharmaceutically acceptable salt thereof.
 13. A compound as claimedin claim 1, wherein the compound is5-[3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxyl-5-pyridyl]propyl]-2,4-oxazolidinedioneor a pharmaceutically acceptable salt.
 14. A compound as claimed inclaim 1, wherein the compound is5-[3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridyl]propyl]-2,4-oxazolidinedioneor a pharmaceutically acceptable salt.
 15. A medicinal composition forthe treatment of diabetes or hyperlipidemia which comprises an effectiveamount of a compound or pharmaceutically acceptable salt thereof asdefined in claim 1, and a pharmaceutically acceptable carrier therefor.16. A medicinal composition according to claim 15 wherein the compoundis of the formula: ##STR101##
 17. A method for treating a mammalsuffering from diabetes or hyperlipidemia, which comprises administeringto the mammal an effective amount of a compound, or a pharmaceuticallyacceptable salt thereof as defined in claim 1.